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'''Ocular albinism type 1''' '''(OA1)''', also called '''Nettleship–Falls syndrome''', is the most common type of [[ocular albinism]], with a prevalence rate of 1:50,000.<ref name="Oetting 2002">{{cite journal|last1=W.S.|first1=Oetting|title=New insights into ocular albinism type 1(OA1): Mutations and polymrphisms of the Oa1 gene|journal=Human Mutation|date=February 2002|volume=19|issue=2|pages=85-92|doi=10.1002/humu.10034|url=http://onlinelibrary.wiley.com/doi/10.1002/humu.10034/full}}</ref><ref name="Incerti 2000">{{cite journal|last1=Incerti|first1=Barbara|title=Oa1 knock-out: New insights on the pathogenesis of ocular albinism type 1|journal=Human Molecular Genetics|date=2000|volume=9|issue=19|pages=2781-2788|doi=10.1093/hmg/9.19.2781|url=http://hmg.oxfordjournals.org/content/9/19/2781.short}}</ref> It is an inheritable classical Mendelian type [[X-linked recessive]] disorder wherein the [[retinal pigment epithelium]] lacks pigment while hair and skin appear normal.<ref>Burns, W.N., Schiaffino, V.M. and Lewis, R.A. (1998). Repeated transmission of X-linked ocular albinism type 1 by a carrier oocyte donor. '''Fertility and Sterility''' ''70(6):''1169.</ref><ref>Carden, S.M., Boissy, R.E., Schoettker, P.J. and Good, W.V. (1998). Albinism: Modern molecular diagnosis. '''British Journal of Ophthalmology''' ''82:''189.</ref> Since it is an X-linked disorder, it occurs mostly in males, while females are carriers unless they are homozygous.<ref name="Shen 2001">{{cite journal|last1=Shen|first1=Bin|title=Ocular albinism 1: More than meets the eye|journal=Pigment Cell Research|date=August 2001|volume=14|issue=4|pages=243-248|doi=10.1034/j.1600-0749.2001.140403.x|url=http://onlinelibrary.wiley.com/doi/10.1034/j.1600-0749.2001.140403.x/full}}</ref> About 60 missense and nonsense mutations, insertions and deletions have been identified in ''Oa1''. Mutations in OA1 have been linked to defective glycosylation and thus improper intracellular transportation.<ref>Schiaffino, M.V., d'Addio, M., Alloni, A., Baschirotto, C., Valetti, C., Cortese, K., Puri, C., Bassi, M.T., Colla, C., De Luca, M., Tacchetti, C. and Ballabio, A. (1999). Ocular albinism: Evidence for a defect in an intracellular signal transduction system. ''Nature Genetics'' '''23:'''108.</ref>
'''Ocular albinism type 1''' '''(OA1)''', also called '''Nettleship–Falls syndrome''', is the most common type of [[ocular albinism]], with a prevalence rate of 1:50,000.<ref>Oetting, W.S. (2002). New insights into ocular albinism type 1(OA1): Mutations and polymorphisms of the ''Oa1'' gene. ''Human Mutations'' '''19:'''85.</ref><ref>Incerti, B., Cortese, K., Pizzigoni, A., Surace, E.M., Varani, S., Coppola, M., Jeffery, G., Seeliger, M., Jaissle, G., Bennett, D.C., Marigo, V., Schiaffino, M.V., Tacchetti, C. and Ballabio, A. (2000). Oa1 knock-out: New insights on the pathogenesis of ocular albinism type 1. ''Human Molecular Genetics'' '''9(19):'''2781.</ref> It is an inheritable classical Mendelian type [[X-linked recessive]] disorder wherein the [[retinal pigment epithelium]] lacks pigment while hair and skin appear normal.<ref>Burns, W.N., Schiaffino, V.M. and Lewis, R.A. (1998). Repeated transmission of X-linked ocular albinism type 1 by a carrier oocyte donor. '''Fertility and Sterility''' ''70(6):''1169.</ref><ref>Carden, S.M., Boissy, R.E., Schoettker, P.J. and Good, W.V. (1998). Albinism: Modern molecular diagnosis. '''British Journal of Ophthalmology''' ''82:''189.</ref> Since it is an X-linked disorder, it occurs mostly in males, while females are carriers unless they are homozygous.<ref>Shen, B., Samaraweera, P., Rosenberg, B. and Orlow, S.J. (2001). Ocular albinism 1: More than meets the eye. ''Pigment Cell Research'' '''14:'''243.</ref> About 60 missense and nonsense mutations, insertions and deletions have been identified in ''Oa1''. Mutations in OA1 have been linked to defective glycosylation and thus improper intracellular transportation.<ref>Schiaffino, M.V., d'Addio, M., Alloni, A., Baschirotto, C., Valetti, C., Cortese, K., Puri, C., Bassi, M.T., Colla, C., De Luca, M., Tacchetti, C. and Ballabio, A. (1999). Ocular albinism: Evidence for a defect in an intracellular signal transduction system. ''Nature Genetics'' '''23:'''108.</ref>


The eponyms of the name "Nettleship–Falls syndrome" are [[Edward Nettleship]] and [[Harold Falls|Harold Francis Falls]].
The eponyms of the name "Nettleship–Falls syndrome" are [[Edward Nettleship]] and [[Harold Falls|Harold Francis Falls]].


==Albinism==
==Albinism==
The term ''[[albinism]]'' [L. ''albus'' means ‘white’] refers to a heterogeneous group of congenital disorders in [[melanin]] pigment biogenesis. Pigmentation process maybe affected in one or many ways due to mutations. Abnormal pigmentation maybe at the level of [[embryogenesis]] in regions where melanocytes fail to populate. The melanin biosynthetic pathway may also be affected due to mutations. Sometimes one or many of the genes responsible for biogenesis of organelles may be mutated.<ref name="Kushimoto 2001">{{cite journal|last1=Kushimoto|first1=Tsuneto|title=A model for melanosome biogenesis based on the purification and analysis of early melanosomes|journal=PNAS|date=2001|volume=98|issue=19|pages=10698-10703|doi=10.1073/pnas.191184798|pmid=11526213|url=http://www.pnas.org/content/98/19/10698?tab=author-info}}</ref>
The term ''[[albinism]]'' [L. ''albus'' means ‘white’] refers to a heterogeneous group of congenital disorders in [[melanin]] pigment biogenesis. Pigmentation process maybe affected in one or many ways due to mutations. Abnormal pigmentation maybe at the level of [[embryogenesis]] in regions where melanocytes fail to populate. The melanin biosynthetic pathway may also be affected due to mutations. Sometimes one or many of the genes responsible for biogenesis of organelles may be mutated.<ref>Kushimoto, T., Basrur, V., Valencia, J., Matsunaga, J., Viera, W.D., Ferrans, V.J., Muller, J., Appella, E. and Hearing, V.J. (2001). A model for melanosome biogenesis based on the purification and analysis of early melanosomes. ''Proceedings at the National Academy of Sciences'' '''98(19):'''10698.</ref>


Albinism may manifest itself as oculocutaneous (OCA) or just ocular (OA). There occur at least ten different types of OCA and four types of OA.<ref name="Incerti 2000" /><ref>Hegde, M., Lewis, R.A. and Richards, C.S. (2002). Diagnostic DNA testing for X-linked ocular albinism (OA1) with a hierarchical mutation screening protocol. ''Genetic Testing'' '''6(1):'''7.</ref> OCA refers to a group of autosomal recessive disorders in which melanin is reduced or even absent leading to pale skin with increased risk of skin cancer. OCA1 is caused due to mutations in tyrosinase gene affecting its catalytic or synthetic activity.<ref name="Kushimoto 2001" /> OCA2 is a condition where ''TYR'' gene is not mutated but the P polypeptide is. Mutational defects in TRP-1 protein leads to OCA3.
Albinism may manifest itself as oculocutaneous (OCA) or just ocular (OA). There occur at least ten different types of OCA and four types of OA.<ref>Incerti, B., Cortese, K., Pizzigoni, A., Surace, E.M., Varani, S., Coppola, M., Jeffery, G., Seeliger, M., Jaissle, G., Bennett, D.C., Marigo, V., Schiaffino, M.V., Tacchetti, C. and Ballabio, A. (2000). Oa1 knock-out: New insights on the pathogenesis of ocular albinism type 1. ''Human Molecular Genetics'' '''9(19):'''2781.</ref><ref>Hegde, M., Lewis, R.A. and Richards, C.S. (2002). Diagnostic DNA testing for X-linked ocular albinism (OA1) with a hierarchical mutation screening protocol. ''Genetic Testing'' '''6(1):'''7.</ref> OCA refers to a group of autosomal recessive disorders in which melanin is reduced or even absent leading to pale skin with increased risk of skin cancer. OCA1 is caused due to mutations in tyrosinase gene affecting its catalytic or synthetic activity.<ref>Kushimoto, T., Basrur, V., Valencia, J., Matsunaga, J., Viera, W.D., Ferrans, V.J., Muller, J., Appella, E. and Hearing, V.J. (2001). A model for melanosome biogenesis based on the purification and analysis of early melanosomes. ''Proceedings at the National Academy of Sciences'' '''98(19):'''10698.</ref> OCA2 is a condition where ''TYR'' gene is not mutated but the P polypeptide is. Mutational defects in TRP-1 protein leads to OCA3.


Ocular albinism results from defects in the melanin system, which may arise from either defects in the OA1 receptor, or mutations of either the Tyr gene or P transporter.<ref name="Kushimoto 2001" />
Ocular albinism results from defects in the melanin system, which may arise from either defects in the OA1 receptor, or mutations of either the Tyr gene or P transporter.<ref>Kushimoto, T., Basrur, V., Valencia, J., Matsunaga, J., Viera, W.D., Ferrans, V.J., Muller, J., Appella, E. and Hearing, V.J. (2001). A model for melanosome biogenesis based on the purification and analysis of early melanosomes. ''Proceedings at the National Academy of Sciences'' '''98(19):'''10698.</ref>


==Symptoms==
==Symptoms==
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==Microscopic examination==
==Microscopic examination==
Microscopic examination of retinal pigment epithelium and skin [[melanocytes]] of patients suffering from OA1 reveal the presence of characteristic macromelanosomes, even though skin appears normal.<ref name="Oetting 1999">{{cite journal|last1=Oetting|first1=Williams S.|title=Molecular basis of albinism: Mutations and polymorphisms of pigmentation genes associated with albinism|journal=Human Mutation|date=1999|volume=13|issue=2|pages=99-115|doi=10.1002/(SICI)1098-1004(1999)13:2<99::AID-HUMU2>3.0.CO;2-C|url=http://onlinelibrary.wiley.com/doi/10.1002/(SICI)1098-1004(1999)13:2%3C99::AID-HUMU2%3E3.0.CO;2-C/full?2-C/full}}</ref> Studies from ''Oa1'' knock-out mice reveal that these giant [[melanosomes]] appear due to abnormal growth of a single melanosome and not due to aggregation or fusion of many melanosomes. These melanin macroglobules are probably formed due to failure of melanosomes to separate from the [[Endoplasmic reticulum|ER]]-[[Golgi apparatus|golgi]] system with the accumulation of enzymes and other secretory proteins leading to an increase organelle size. However, Incerti, ''et al.'' contradict the above theory.<ref name="Incerti 2000" />
Microscopic examination of retinal pigment epithelium and skin [[melanocytes]] of patients suffering from OA1 reveal the presence of characteristic macromelanosomes, even though skin appears normal.<ref>Oetting, W.S. and King, R. A.(1999). Molecular basis of albinism: Mutations and polymorphisms of pigmented genes associated with albinism. ''Human Mutations'' '''13:'''99.</ref> Studies from ''Oa1'' knock-out mice reveal that these giant [[melanosomes]] appear due to abnormal growth of a single melanosome and not due to aggregation or fusion of many melanosomes. These melanin macroglobules are probably formed due to failure of melanosomes to separate from the [[Endoplasmic reticulum|ER]]-[[Golgi apparatus|golgi]] system with the accumulation of enzymes and other secretory proteins leading to an increase organelle size. However, Incerti, ''et al.'' contradict the above theory.<ref>Incerti, B., Cortese, K., Pizzigoni, A., Surace, E.M., Varani, S., Coppola, M., Jeffery, G., Seeliger, M., Jaissle, G., Bennett, D.C., Marigo, V., Schiaffino, M.V., Tacchetti, C. and Ballabio, A. (2000). Oa1 knock-out: New insights on the pathogenesis of ocular albinism type 1. ''Human Molecular Genetics'' '''9(19):'''2781.</ref>


==Treatment==
==Treatment==
To date there is no treatment for ocular albinism, probably because such little is known about the receptor function and its role in pathophysiology. Though surgery for strabismus is sometimes helpful, there does not seem to be a sure remedy for it until the etiology of ocular albinism is well established.<ref>http://www.albinism.org/publications/ocular.html</ref> However, with the recent discovery of the upstream ligand (L-DOPA) and the discovery of Oa1's possible downstream G alpha partner (Gai3) the Oa1 pathway is becoming clearer and future of Oa1 research looks promising.<ref name="Lopez 2008">{{cite journal|last1=Lopez|first1=Vanessa M|title=L-DOPA Is an Endogenous Ligand for OA1|journal=PLoS Biology|date=2008|volume=6|issue=9|page=e236|doi=10.1371/journal.pbio.0060236|url=http://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.0060236}}</ref>
To date there is no treatment for ocular albinism, probably because such little is known about the receptor function and its role in pathophysiology. Though surgery for strabismus is sometimes helpful, there does not seem to be a sure remedy for it until the etiology of ocular albinism is well established.<ref>http://www.albinism.org/publications/ocular.html</ref> However, with the recent discovery of the upstream ligand (L-DOPA) and the discovery of Oa1's possible downstream G alpha partner (Gai3) the Oa1 pathway is becoming clearer and future of Oa1 research looks promising.<ref><37>(uncovering the OA1 signaling pathway, Lopez, V.M., Decatur, C.L., Stamer, W.D., Lynch, R.M. and McKay, B.S. (2008). L-DOPA is an endogenous ligand for OA1. ''PLoS Biology'' '''6(9):'''e236.</ref>


Touloukian ''et al.'' have characterized OA1 immunologically as a melanoma/melanocyte differentiation antigen.<ref>Shen, B., Rosenberg, B. and Orlow, S.J. (2001). Intracellular distribution and late endosomal effects of the ocular albinism type 1 gene product: Consequences of disease-causing mutations and implications for melanosome biogenesis. ''Traffic'' '''2:'''202.</ref> Flow cytometry data suggests that OA1-specific T cells are all CD8+. This indicates that OA1 peptide is processed and presented on the surface of melanoma cells to be recognized by antigen-specific T cells. Moreover, recognition of OA1 by T cells induces cytokine production by the OA1-specific T cells.This means that OA1 is a potential target for melanoma vaccines.
Touloukian ''et al.'' have characterized OA1 immunologically as a melanoma/melanocyte differentiation antigen.<ref>Shen, B., Rosenberg, B. and Orlow, S.J. (2001). Intracellular distribution and late endosomal effects of the ocular albinism type 1 gene product: Consequences of disease-causing mutations and implications for melanosome biogenesis. ''Traffic'' '''2:'''202.</ref> Flow cytometry data suggests that OA1-specific T cells are all CD8+. This indicates that OA1 peptide is processed and presented on the surface of melanoma cells to be recognized by antigen-specific T cells. Moreover, recognition of OA1 by T cells induces cytokine production by the OA1-specific T cells.This means that OA1 is a potential target for melanoma vaccines.


==Molecular biology of ''Oa1''==
==Molecular biology of ''Oa1''==
Human ''Oa1'' gene has been identified by positional cloning as a 40kb gene mapped to Xp22.3-Xp22.2.<ref name="Shen 2001" /><ref name="Oetting 1999" /> Later, a mouse homolog of the human ''Oa1'' gene was also identified and cloned. It codes for a 404 amino acid long protein with up to three potential glycosylation sites. The transcript has been found to be expressing very well in retinal pigment epithelium and skin and to a much lesser extent in brain and adrenal glands.<ref name="Oetting 1999" />
Human ''Oa1'' gene has been identified by positional cloning as a 40kb gene mapped to Xp22.3-Xp22.2.<ref>Shen, B., Samaraweera, P., Rosenberg, B. and Orlow, S.J. (2001). Ocular albinism 1: More than meets the eye. ''Pigment Cell Research'' '''14:'''243.</ref><ref>Oetting, W.S. and King, R. A.(1999). Molecular basis of albinism: Mutations and polymorphisms of pigmented genes associated with albinism. ''Human Mutations'' '''13:'''99.</ref> Later, a mouse homolog of the human ''Oa1'' gene was also identified and cloned. It codes for a 404 amino acid long protein with up to three potential glycosylation sites. The transcript has been found to be expressing very well in retinal pigment epithelium and skin and to a much lesser extent in brain and adrenal glands.<ref>Oetting, W.S. and King, R. A.(1999). Molecular basis of albinism: Mutations and polymorphisms of pigmented genes associated with albinism. ''Human Mutations'' '''13:'''99.</ref>


Mutations in ''Oa1'' have been well characterized and studied using various techniques like [[southern blot]] analyses, [[single-strand conformation polymorphism]] and sequence analysis.<ref>Hegde, M., Lewis, R.A. and Richards, C.S. (2002). Diagnostic DNA testing for X-linked ocular albinism (OA1) with a hierarchical mutation screening protocol. ''Genetic Testing'' '''6(1):'''7.</ref> Most of these mutations have been reported to be occurring in the N-terminus and few in the trans-membrane regions but very rarely in the much conserved cytoplasmic C-terminus. Populations belonging to different ethnic groups have been extensively analyzed and a database has been created recording the details of mutations related to OA1.<ref>http://www.cbc.umm.edu/tad</ref> A total of 25 missense, 2 nonsense, 9 frameshift, and 5 splicing mutations have been reported till date.<ref name="Oetting 1999" /> In addition to these mutations, there also occur several deletions in one or many of the exons of ''Oa1'' gene, especially exon 2. These deletions are presumed to be because of unequal crossing-over due to the presence of flanking ''Alu'' regions. In some cases, the entire ''Oa1'' gene is deleted along with other contiguous genes. Many different polymorphisms have also been detected, mainly in intron 1.<ref name="Oetting 1999" />
Mutations in ''Oa1'' have been well characterized and studied using various techniques like [[southern blot]] analyses, [[single-strand conformation polymorphism]] and sequence analysis.<ref>Hegde, M., Lewis, R.A. and Richards, C.S. (2002). Diagnostic DNA testing for X-linked ocular albinism (OA1) with a hierarchical mutation screening protocol. ''Genetic Testing'' '''6(1):'''7.</ref> Most of these mutations have been reported to be occurring in the N-terminus and few in the trans-membrane regions but very rarely in the much conserved cytoplasmic C-terminus. Populations belonging to different ethnic groups have been extensively analyzed and a database has been created recording the details of mutations related to OA1.<ref>http://www.cbc.umm.edu/tad</ref> A total of 25 missense, 2 nonsense, 9 frameshift, and 5 splicing mutations have been reported till date.<ref>Oetting, W.S. and King, R. A.(1999). Molecular basis of albinism: Mutations and polymorphisms of pigmented genes associated with albinism. ''Human Mutations'' '''13:'''99.</ref> In addition to these mutations, there also occur several deletions in one or many of the exons of ''Oa1'' gene, especially exon 2. These deletions are presumed to be because of unequal crossing-over due to the presence of flanking ''Alu'' regions. In some cases, the entire ''Oa1'' gene is deleted along with other contiguous genes. Many different polymorphisms have also been detected, mainly in intron 1.<ref>Oetting, W.S. and King, R. A.(1999). Molecular basis of albinism: Mutations and polymorphisms of pigmented genes associated with albinism. ''Human Mutations'' '''13:'''99.</ref>


Tissue-specific control of ''Oa1'' transcription is by a 617bp long E-box region bound by Mitf.<ref>Vetrini, F., Auricchio, A., Du, J., Angeletti, B., Fisher, D.E., Ballabio, A. and Marigo, V. (2004). The microphthalmis transcription factor (Mitf) controls expression of the ocular albinism type 1 gene: Link between melanin synthesis and melanosome biogenesis. ''Molecular and Cellular Biology'' '''24(15):'''6550.</ref> Mitf has been shown to regulate expression of many melanosomal genes like TYR and TRP-1 through the E-box motif (CATGTG). Vetrini ''et al.'' have used adenoviral vectors to study tissue-specificity of ''Oa1'' transcription through Mitf and observed that this regulation in conserved in human ''Oa1'' gene.<ref>Vetrini, F., Auricchio, A., Du, J., Angeletti, B., Fisher, D. E., Ballabio, A., Marigo, V. (2004). The microphthalmis transcription factor (Mitf) controls expression of the ocular albinism type 1 gene: link between melanin synthesis and melanosome biogenesis. Mol Cell Biol 24(15): 6550</ref>
Tissue-specific control of ''Oa1'' transcription is by a 617bp long E-box region bound by Mitf.<ref>Vetrini, F., Auricchio, A., Du, J., Angeletti, B., Fisher, D.E., Ballabio, A. and Marigo, V. (2004). The microphthalmis transcription factor (Mitf) controls expression of the ocular albinism type 1 gene: Link between melanin synthesis and melanosome biogenesis. ''Molecular and Cellular Biology'' '''24(15):'''6550.</ref> Mitf has been shown to regulate expression of many melanosomal genes like TYR and TRP-1 through the E-box motif (CATGTG). Vetrini ''et al.'' have used adenoviral vectors to study tissue-specificity of ''Oa1'' transcription through Mitf and observed that this regulation in conserved in human ''Oa1'' gene.<ref>Vetrini, F., Auricchio, A., Du, J., Angeletti, B., Fisher, D. E., Ballabio, A., Marigo, V. (2004). The microphthalmis transcription factor (Mitf) controls expression of the ocular albinism type 1 gene: link between melanin synthesis and melanosome biogenesis. Mol Cell Biol 24(15): 6550</ref>


==Structure of OA1 protein==
==Structure of OA1 protein==
Human ''Oa1'' gene product was initially identified as a 60kDa protein formed from a 46-48kDa precursor.<ref name="Shen 2001" /> The OA1 disease is due to defect in the OA1 receptor. This receptor has been shown to be similar to class C [[G protein-coupled receptor|G- protein coupled receptors]] (GPCR). OA1 receptor has a characteristic GPCR structure-7 transmembrane helices with 3 cytoplasmic loops and 3 extracellular loops and an extracellular N- terminus and cytoplasmic C-terminus. Recently the ligand activating this receptor was found.<ref name="Lopez 2008" /> A recent computational work has provided some insight into the three-dimensional structure of this protein and its dynamic interactions with its known ligands.<ref>Ghosh, A., Sonavane, U., Andhirka, S.K., Aradhyam, G.K., Joshi, R. (2012). Structural insights into human GPCR protein OA1: a computational perspective. ''Journal of Molecular Modeling'' '''18(5):2117'''.</ref>
Human ''Oa1'' gene product was initially identified as a 60kDa protein formed from a 46-48kDa precursor.<ref>Shen, B., Samaraweera, P., Rosenberg, B. and Orlow, S.J. (2001). Ocular albinism 1: More than meets the eye. ''Pigment Cell Research'' '''14:'''243.</ref> The OA1 disease is due to defect in the OA1 receptor. This receptor has been shown to be similar to class C [[G protein-coupled receptor|G- protein coupled receptors]] (GPCR). OA1 receptor has a characteristic GPCR structure-7 transmembrane helices with 3 cytoplasmic loops and 3 extracellular loops and an extracellular N- terminus and cytoplasmic C-terminus. Recently the ligand activating this receptor was found.<ref>Lopez, V.M., Decatur, C.L., Stamer, W.D., Lynch, R.M. and McKay, B.S. (2008). L-DOPA is an endogenous ligand for OA1. ''PLoS Biology'' '''6(9):'''e236.</ref> A recent computational work has provided some insight into the three-dimensional structure of this protein and its dynamic interactions with its known ligands.<ref>Ghosh, A., Sonavane, U., Andhirka, S.K., Aradhyam, G.K., Joshi, R. (2012). Structural insights into human GPCR protein OA1: a computational perspective. ''Journal of Molecular Modeling'' '''18(5):2117'''.</ref>


==Localization of the OA1 protein==
==Localization of the OA1 protein==
Shen, ''et al.'' created fusion proteins between OA1 and GFP.<ref name="Shen 2001" /> Melanosomal localization of OA1 has been confirmed by immuno-electron microscopy and other techniques alike. Localization patterns of wild type OA1-GFP and mutated OA1-GFP were compared. The wild type OA1 localized to late endosomal or lysosomal compartments. This is supported by data from Samaraweera, ''et al.'' that OA1 colocalizes with Lamp1, which is a marker for late endosomal compartment. Hence, OA1 might traffick itself out of this compartment to the melanosomes.<ref name="Samaraweera">{{cite journal|last1=Samaraweera|first1=Preminda|title=The Mouse Ocular Albinism 1 Gene Product is an Endolysosomal Protein|journal=Experimental Eye Research|date=2001|volume=72|issue=3|pages=319-329|doi=10.1006/exer.2000.0962|url=http://www.sciencedirect.com/science/article/pii/S001448350090962X}}</ref>
Shen, ''et al.'' created fusion proteins between OA1 and GFP.<ref>Shen, B., Samaraweera, P., Rosenberg, B. and Orlow, S.J. (2001). Ocular albinism 1: More than meets the eye. ''Pigment Cell Research'' '''14:'''243.</ref> Melanosomal localization of OA1 has been confirmed by immuno-electron microscopy and other techniques alike. Localization patterns of wild type OA1-GFP and mutated OA1-GFP were compared. The wild type OA1 localized to late endosomal or lysosomal compartments. This is supported by data from Samaraweera, ''et al.'' that OA1 colocalizes with Lamp1, which is a marker for late endosomal compartment. Hence, OA1 might traffick itself out of this compartment to the melanosomes.<ref>Samaraweera, P., Shen, B., Newton, J.M., Barsh, G.S. and Orlow, S.J. (2001). The mouse ocular albinism 1 gene product is an endolysosomal protein. ''Experimental Eye Research'' '''72:'''319.</ref>


In addition to retina and melanoma, OA1 protein product was also detected in human pigment cells like melanosomal membrane glycoprotein.<ref name="Incerti 2000" /> This suggests that OA1 might be involved in melanosome biogenesis. Coimmunoprecipitation studies of OA1 with G<sub>β</sub> and G<sub>αi</sub> in melanocyte extracts revealed its specific interaction with G<sub>αi</sub>.<ref name="Oetting 2002" /> Further study have also shown that OA1 interact specifically with G<sub>αi3</sub> subtype.<ref>{{Cite journal|title = Involvement of OA1, an Intracellular GPCR, and Gαi3, Its Binding Protein, in Melanosomal Biogenesis and Optic Pathway Formation|journal = Investigative ophthalmology & visual science|date = 2008-07-01|issn = 0146-0404|pmc = 2881626|pmid = 18378571|pages = 3245–3252|volume = 49|issue = 7|doi = 10.1167/iovs.08-1806|first = Alejandra|last = Young|first2 = Elisabeth B.|last2 = Powelson|first3 = Irene E.|last3 = Whitney|first4 = Mary A.|last4 = Raven|first5 = Steven|last5 = Nusinowitz|first6 = Meisheng|last6 = Jiang|first7 = Lutz|last7 = Birnbaumer|first8 = Benjamin E.|last8 = Reese|first9 = Debora B.|last9 = Farber}}</ref><ref>{{Cite journal|title = Specific Interaction of Gαi3 with the Oa1 G-Protein Coupled Receptor Controls the Size and Density of Melanosomes in Retinal Pigment Epithelium|url = http://dx.doi.org/10.1371/journal.pone.0024376|journal = PLoS ONE|date = 2011-09-08|pmc = 3169599|pmid = 21931697|pages = e24376|volume = 6|issue = 9|doi = 10.1371/journal.pone.0024376|first = Alejandra|last = Young|first2 = Meisheng|last2 = Jiang|first3 = Ying|last3 = Wang|first4 = Novruz B.|last4 = Ahmedli|first5 = John|last5 = Ramirez|first6 = Benjamin E.|last6 = Reese|first7 = Lutz|last7 = Birnbaumer|first8 = Debora B.|last8 = Farber}}</ref><ref>{{Cite journal|title = A Constitutively Active Gαi3 Protein Corrects the Abnormal Retinal Pigment Epithelium Phenotype of Oa1−/− mice|url = http://dx.doi.org/10.1371/journal.pone.0076240|journal = PLoS ONE|date = 2013-09-30|pmc = 3787026|pmid = 24098784|pages = e76240|volume = 8|issue = 9|doi = 10.1371/journal.pone.0076240|first = Alejandra|last = Young|first2 = Ying|last2 = Wang|first3 = Novruz B.|last3 = Ahmedli|first4 = Meisheng|last4 = Jiang|first5 = Debora B.|last5 = Farber}}</ref> Moreover, since OA1 is an organellar GPCR, it may represent an unidentified pathway in the melanosome. Until recently, it was believed that the probable ligand for OA1 might be within the melanosomal lumen, maybe one of the components of the melanogenic pathway since it is so closely related to melanosome biogenesis.<ref name="Incerti 2000" /> This has been proved now.<ref name="Lopez 2008" />
In addition to retina and melanoma, OA1 protein product was also detected in human pigment cells like melanosomal membrane glycoprotein.<ref>Incerti, B., Cortese, K., Pizzigoni, A., Surace, E.M., Varani, S., Coppola, M., Jeffery, G., Seeliger, M., Jaissle, G., Bennett, D.C., Marigo, V., Schiaffino, M.V., Tacchetti, C. and Ballabio, A. (2000). Oa1 knock-out: New insights on the pathogenesis of ocular albinism type 1. ''Human Molecular Genetics'' '''9(19):'''2781.</ref> This suggests that OA1 might be involved in melanosome biogenesis. Coimmunoprecipitation studies of OA1 with G<sub>β</sub> and G<sub>αi</sub> in melanocyte extracts revealed its specific interaction with G<sub>αi</sub>.<ref>Oetting, W.S. (2002). New insights into ocular albinism type 1(OA1): Mutations and polymorphisms of the ''Oa1'' gene. ''Human Mutations'' '''19:'''85.</ref> Further study have also shown that OA1 interact specifically with G<sub>αi3</sub> subtype.<ref>{{Cite journal|title = Involvement of OA1, an Intracellular GPCR, and Gαi3, Its Binding Protein, in Melanosomal Biogenesis and Optic Pathway Formation|journal = Investigative ophthalmology & visual science|date = 2008-07-01|issn = 0146-0404|pmc = 2881626|pmid = 18378571|pages = 3245–3252|volume = 49|issue = 7|doi = 10.1167/iovs.08-1806|first = Alejandra|last = Young|first2 = Elisabeth B.|last2 = Powelson|first3 = Irene E.|last3 = Whitney|first4 = Mary A.|last4 = Raven|first5 = Steven|last5 = Nusinowitz|first6 = Meisheng|last6 = Jiang|first7 = Lutz|last7 = Birnbaumer|first8 = Benjamin E.|last8 = Reese|first9 = Debora B.|last9 = Farber}}</ref><ref>{{Cite journal|title = Specific Interaction of Gαi3 with the Oa1 G-Protein Coupled Receptor Controls the Size and Density of Melanosomes in Retinal Pigment Epithelium|url = http://dx.doi.org/10.1371/journal.pone.0024376|journal = PLoS ONE|date = 2011-09-08|pmc = 3169599|pmid = 21931697|pages = e24376|volume = 6|issue = 9|doi = 10.1371/journal.pone.0024376|first = Alejandra|last = Young|first2 = Meisheng|last2 = Jiang|first3 = Ying|last3 = Wang|first4 = Novruz B.|last4 = Ahmedli|first5 = John|last5 = Ramirez|first6 = Benjamin E.|last6 = Reese|first7 = Lutz|last7 = Birnbaumer|first8 = Debora B.|last8 = Farber}}</ref><ref>{{Cite journal|title = A Constitutively Active Gαi3 Protein Corrects the Abnormal Retinal Pigment Epithelium Phenotype of Oa1−/− mice|url = http://dx.doi.org/10.1371/journal.pone.0076240|journal = PLoS ONE|date = 2013-09-30|pmc = 3787026|pmid = 24098784|pages = e76240|volume = 8|issue = 9|doi = 10.1371/journal.pone.0076240|first = Alejandra|last = Young|first2 = Ying|last2 = Wang|first3 = Novruz B.|last3 = Ahmedli|first4 = Meisheng|last4 = Jiang|first5 = Debora B.|last5 = Farber}}</ref> Moreover, since OA1 is an organellar GPCR, it may represent an unidentified pathway in the melanosome. Until recently, it was believed that the probable ligand for OA1 might be within the melanosomal lumen, maybe one of the components of the melanogenic pathway since it is so closely related to melanosome biogenesis.<ref>Incerti, B., Cortese, K., Pizzigoni, A., Surace, E.M., Varani, S., Coppola, M., Jeffery, G., Seeliger, M., Jaissle, G., Bennett, D.C., Marigo, V., Schiaffino, M.V., Tacchetti, C. and Ballabio, A. (2000). Oa1 knock-out: New insights on the pathogenesis of ocular albinism type 1. ''Human Molecular Genetics'' '''9(19):'''2781.</ref> This has been proved now.<ref>Lopez, V.M., Decatur, C.L., Stamer, W.D., Lynch, R.M. and McKay, B.S. (2008). L-DOPA is an endogenous ligand for OA1. ''PLoS Biology'' '''6(9):'''e236.</ref>


Studies by Samaraweera, ''et al.'' revealed OA1 as an endolysosomal protein.<ref>Samaraweera, P., Shen, B., Newton, J.M., Barsh, G.S. and Orlow, S.J. (2001). The mouse ocular albinism 1 gene product is an endolysosomal protein. ''Experimental Eye Research'' '''72:'''319.</ref> Schiaffino, ''et al.'' already proved that it is an integral membrane protein.<ref>Schiaffino, M.V., d'Addio, M., Alloni, A., Baschirotto, C., Valetti, C., Cortese, K., Puri, C., Bassi, M.T., Colla, C., De Luca, M., Tacchetti, C. and Ballabio, A. (1999). Ocular albinism: Evidence for a defect in an intracellular signal transduction system. ''Nature Genetics'' '''23:'''108.</ref> Newton ''et al.'' have shown that it has three probable glycosylation sites.<ref>Newton, J.M., Orlow, S.J. and Barsh, G.S. (1996). Isolation and characterization of a mouse homolog of the X-linked ocular albinism (OA1) gene. ''Genomics'' '''37:'''219.</ref> Furthermore, OA1 was found to be stimulated by α-melanocortin stimulating hormone but inhibited by agouti signal protein.<ref>Samaraweera, P., Shen, B., Newton, J.M., Barsh, G.S. and Orlow, S.J. (2001). The mouse ocular albinism 1 gene product is an endolysosomal protein. ''Experimental Eye Research'' '''72:'''319.</ref> The fact that OA1 responds to melanin modifiers indicates its probable role in melanogenesis. Just like other melanosomal proteins TYR and TRP-1, processing of OA1 also occurs in the golgi.<ref>d'Addio, M., Pizzigoni, A., Bassi, M.T., Baschirotto, C., Valetti, C., Incerti, B., Clementi, M., De Luca, M., Ballabio, A. and Schiaffino, M.V. (2000). Defective intracellular transport and processing of OA1 is a major cause of ocular albinism type 1. ''Human Molecular Genetics'' '''9(20):'''3011.</ref> Endogenous OA1 protein expressed by normal human melanocytes is detected as a 60kDa protein.
Studies by Samaraweera, ''et al.'' revealed OA1 as an endolysosomal protein.<ref>Samaraweera, P., Shen, B., Newton, J.M., Barsh, G.S. and Orlow, S.J. (2001). The mouse ocular albinism 1 gene product is an endolysosomal protein. ''Experimental Eye Research'' '''72:'''319.</ref> Schiaffino, ''et al.'' already proved that it is an integral membrane protein.<ref>Schiaffino, M.V., d'Addio, M., Alloni, A., Baschirotto, C., Valetti, C., Cortese, K., Puri, C., Bassi, M.T., Colla, C., De Luca, M., Tacchetti, C. and Ballabio, A. (1999). Ocular albinism: Evidence for a defect in an intracellular signal transduction system. ''Nature Genetics'' '''23:'''108.</ref> Newton ''et al.'' have shown that it has three probable glycosylation sites.<ref>Newton, J.M., Orlow, S.J. and Barsh, G.S. (1996). Isolation and characterization of a mouse homolog of the X-linked ocular albinism (OA1) gene. ''Genomics'' '''37:'''219.</ref> Furthermore, OA1 was found to be stimulated by α-melanocortin stimulating hormone but inhibited by agouti signal protein.<ref>Samaraweera, P., Shen, B., Newton, J.M., Barsh, G.S. and Orlow, S.J. (2001). The mouse ocular albinism 1 gene product is an endolysosomal protein. ''Experimental Eye Research'' '''72:'''319.</ref> The fact that OA1 responds to melanin modifiers indicates its probable role in melanogenesis. Just like other melanosomal proteins TYR and TRP-1, processing of OA1 also occurs in the golgi.<ref>d'Addio, M., Pizzigoni, A., Bassi, M.T., Baschirotto, C., Valetti, C., Incerti, B., Clementi, M., De Luca, M., Ballabio, A. and Schiaffino, M.V. (2000). Defective intracellular transport and processing of OA1 is a major cause of ocular albinism type 1. ''Human Molecular Genetics'' '''9(20):'''3011.</ref> Endogenous OA1 protein expressed by normal human melanocytes is detected as a 60kDa protein.


==Receptor-Ligand interactions==
==Receptor-Ligand interactions==
Very recently the orphan OA1 receptor has been de-orphaned. Studies showed that L-DOPA is the specific ligand for the OA1 receptor.<ref>Gross, L. (2008). A molecular link between albinism and visual deficits. ''PLoS Biology'' '''6(9):'''e248.</ref> L-DOPA is a by-product of melanin biosynthetic pathway. During melanin synthesis, L-DOPA is released to the retina in the retinal pigment epithelium and is necessary for specific stages of retinal development. Activation of the OA1 receptor by L-DOPA leads to the secretion of a neurotropic factor by the retinal pigment epithelium that helps in normal retinal development.<ref name="Lopez 2008" />
Very recently the orphan OA1 receptor has been de-orphaned. Studies showed that L-DOPA is the specific ligand for the OA1 receptor.<ref>Gross, L. (2008). A molecular link between albinism and visual deficits. ''PLoS Biology'' '''6(9):'''e248.</ref> L-DOPA is a by-product of melanin biosynthetic pathway. During melanin synthesis, L-DOPA is released to the retina in the retinal pigment epithelium and is necessary for specific stages of retinal development. Activation of the OA1 receptor by L-DOPA leads to the secretion of a neurotropic factor by the retinal pigment epithelium that helps in normal retinal development.<ref>Lopez, V.M., Decatur, C.L., Stamer, W.D., Lynch, R.M. and McKay, B.S. (2008). L-DOPA is an endogenous ligand for OA1. ''PLoS Biology'' '''6(9):'''e236.</ref>


==Mutations==
==Mutations==
The OA1 mutants were classified into two major groups based on glycosylation and localization patterns. While group I consisted of normally glycosylated OA1, group II represented aberrantly glycosylated OA1 which is indistinguishable from the wild type.<ref name="Shen 2001" /> However, both these studies revealed that in >60% of these mutations, the protein was retained in the ER and which is assumed to be the major cause of OA1. They also revealed that the protein levels decreased drastically, probably due to misfolding of the protein in the ER. Some of the mutations reported in second and third cytoplasmic loops (these regions are known to be critical for GPCR downstream signaling) are believed to affect transduction of the signals from OA1 via G proteins.<ref name="Shen 2001" /><ref>d'Addio, M., Pizzigoni, A., Bassi, M.T., Baschirotto, C., Valetti, C., Incerti, B., Clementi, M., De Luca, M., Ballabio, A. and Schiaffino, M.V. (2000). Defective intracellular transport and processing of OA1 is a major cause of ocular albinism type 1. ''Human Molecular Genetics'' '''9(20):'''3011.</ref>
The OA1 mutants were classified into two major groups based on glycosylation and localization patterns. While group I consisted of normally glycosylated OA1, group II represented aberrantly glycosylated OA1 which is indistinguishable from the wild type.<ref>Shen, B., Samaraweera, P., Rosenberg, B. and Orlow, S.J. (2001). Ocular albinism 1: More than meets the eye. ''Pigment Cell Research'' '''14:'''243.</ref> However, both these studies revealed that in >60% of these mutations, the protein was retained in the ER and which is assumed to be the major cause of OA1. They also revealed that the protein levels decreased drastically, probably due to misfolding of the protein in the ER. Some of the mutations reported in second and third cytoplasmic loops (these regions are known to be critical for GPCR downstream signaling) are believed to affect transduction of the signals from OA1 via G proteins.<ref>Shen, B., Samaraweera, P., Rosenberg, B. and Orlow, S.J. (2001). Ocular albinism 1: More than meets the eye. ''Pigment Cell Research'' '''14:'''243.</ref><ref>d'Addio, M., Pizzigoni, A., Bassi, M.T., Baschirotto, C., Valetti, C., Incerti, B., Clementi, M., De Luca, M., Ballabio, A. and Schiaffino, M.V. (2000). Defective intracellular transport and processing of OA1 is a major cause of ocular albinism type 1. ''Human Molecular Genetics'' '''9(20):'''3011.</ref>


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==Functions of OA1==
==Functions of OA1==
Though the exact role of OA1 is yet to be confirmed, many studies give clues about the probable roles of OA1. The ''Oa1'' gene product might be involved in vesicular trafficking or sorting them to the melanosomes.<ref>Samaraweera, P., Shen, B., Newton, J.M., Barsh, G.S. and Orlow, S.J. (2001). The mouse ocular albinism 1 gene product is an endolysosomal protein. ''Experimental Eye Research'' '''72:'''319.</ref> It is also believed to be involved in redistribution of mannose-6-phosphate receptors, thus suggesting that it is important for melanogensis.<ref name="Oetting 2002" /> Literature shows that it plays a major role in the final stages of growth and maturation of melanosomes. This conclusion is based on the fact that there are no intermediates of melanosome-melanosome fusion and the number of melanosomes decreases only on maturation of the cell and not in the initial stages of development. A number of genes in Drosophila, like the ''hook'' gene that alter ocular pigment granules have been shown to affect lysosomal delivery.<ref name="Oetting 1999" /> Moreover, it has been found that in normal conditions, melanosomal proteins traffic normally to late endosomes, while in the absence of OA1, they continue to accumulate in the mature melanosomes. This may mean that OA1 acts as a stop signal for melanosomal growth.<ref>Shen, B., Rosenberg, B., and Orlow, S.J. (2001). Intracellular distribution and late endosomal effects of the ocular albinism type 1 gene product: Consequences of disease-causing mutations and implications for melanosome biogenesis. ''Traffic'' '''2:'''202.</ref>
Though the exact role of OA1 is yet to be confirmed, many studies give clues about the probable roles of OA1. The ''Oa1'' gene product might be involved in vesicular trafficking or sorting them to the melanosomes.<ref>Samaraweera, P., Shen, B., Newton, J.M., Barsh, G.S. and Orlow, S.J. (2001). The mouse ocular albinism 1 gene product is an endolysosomal protein. ''Experimental Eye Research'' '''72:'''319.</ref> It is also believed to be involved in redistribution of mannose-6-phosphate receptors, thus suggesting that it is important for melanogensis.<ref>Oetting, W.S. (2002). New insights into ocular albinism type 1(OA1): Mutations and polymorphisms of the ''Oa1'' gene. ''Human Mutations'' '''19:'''85.</ref> Literature shows that it plays a major role in the final stages of growth and maturation of melanosomes. This conclusion is based on the fact that there are no intermediates of melanosome-melanosome fusion and the number of melanosomes decreases only on maturation of the cell and not in the initial stages of development. A number of genes in Drosophila, like the ''hook'' gene that alter ocular pigment granules have been shown to affect lysosomal delivery.<ref>Oetting, W.S. and King, R. A.(1999). Molecular basis of albinism: Mutations and polymorphisms of pigmented genes associated with albinism. ''Human Mutations'' '''13:'''99.</ref> Moreover, it has been found that in normal conditions, melanosomal proteins traffic normally to late endosomes, while in the absence of OA1, they continue to accumulate in the mature melanosomes. This may mean that OA1 acts as a stop signal for melanosomal growth.<ref>Shen, B., Rosenberg, B., and Orlow, S.J. (2001). Intracellular distribution and late endosomal effects of the ocular albinism type 1 gene product: Consequences of disease-causing mutations and implications for melanosome biogenesis. ''Traffic'' '''2:'''202.</ref>


==External links==
==External links==

Revision as of 03:05, 20 July 2016

Ocular albinism type 1
SpecialtyEndocrinology Edit this on Wikidata

Ocular albinism type 1 (OA1), also called Nettleship–Falls syndrome, is the most common type of ocular albinism, with a prevalence rate of 1:50,000.[1][2] It is an inheritable classical Mendelian type X-linked recessive disorder wherein the retinal pigment epithelium lacks pigment while hair and skin appear normal.[3][4] Since it is an X-linked disorder, it occurs mostly in males, while females are carriers unless they are homozygous.[5] About 60 missense and nonsense mutations, insertions and deletions have been identified in Oa1. Mutations in OA1 have been linked to defective glycosylation and thus improper intracellular transportation.[6]

The eponyms of the name "Nettleship–Falls syndrome" are Edward Nettleship and Harold Francis Falls.

Albinism

The term albinism [L. albus means ‘white’] refers to a heterogeneous group of congenital disorders in melanin pigment biogenesis. Pigmentation process maybe affected in one or many ways due to mutations. Abnormal pigmentation maybe at the level of embryogenesis in regions where melanocytes fail to populate. The melanin biosynthetic pathway may also be affected due to mutations. Sometimes one or many of the genes responsible for biogenesis of organelles may be mutated.[7]

Albinism may manifest itself as oculocutaneous (OCA) or just ocular (OA). There occur at least ten different types of OCA and four types of OA.[8][9] OCA refers to a group of autosomal recessive disorders in which melanin is reduced or even absent leading to pale skin with increased risk of skin cancer. OCA1 is caused due to mutations in tyrosinase gene affecting its catalytic or synthetic activity.[10] OCA2 is a condition where TYR gene is not mutated but the P polypeptide is. Mutational defects in TRP-1 protein leads to OCA3.

Ocular albinism results from defects in the melanin system, which may arise from either defects in the OA1 receptor, or mutations of either the Tyr gene or P transporter.[11]

Symptoms

OA1 is recognized by many different symptoms. Reduced visual acuity is accompanied by involuntary movements of the eye termed as nystagmus. Astigmatism is a condition wherein there occurs significant refractive error. Moreover, ocular albino eyes become crossed, a condition called as ‘lazy eyes’ or strabismus. Since very little pigment is present the iris becomes translucent and reflects light back. It appears green to blueish red. However, the most important part of the eye, the fovea which is responsible for acute vision, does not develop properly, probably indicating the role of melanin in the development stages of the eye. Some patients may also develop photophobia/photodysphoria. All these symptoms are due to hypo-pigmentation of the retina. Moreover, in an ocular albino eye, nerves from back of the eye to the brain may not follow usual pattern of routing. In an ocular albino eye, more nerves cross from back of the eye to the opposite side of the brain instead of going to the both sides of the brain as in a normal eye.[12] An ocular albino eye appears blueish pink in color with no pigmentation at all unlike a normal eye. Carrier women have regions of hypo- and hyper-pigmentation due to X-inactivation and partial iris transillumination and do not show any other symptoms exhibited by patients suffering from OA1.[13][14]

Microscopic examination

Microscopic examination of retinal pigment epithelium and skin melanocytes of patients suffering from OA1 reveal the presence of characteristic macromelanosomes, even though skin appears normal.[15] Studies from Oa1 knock-out mice reveal that these giant melanosomes appear due to abnormal growth of a single melanosome and not due to aggregation or fusion of many melanosomes. These melanin macroglobules are probably formed due to failure of melanosomes to separate from the ER-golgi system with the accumulation of enzymes and other secretory proteins leading to an increase organelle size. However, Incerti, et al. contradict the above theory.[16]

Treatment

To date there is no treatment for ocular albinism, probably because such little is known about the receptor function and its role in pathophysiology. Though surgery for strabismus is sometimes helpful, there does not seem to be a sure remedy for it until the etiology of ocular albinism is well established.[17] However, with the recent discovery of the upstream ligand (L-DOPA) and the discovery of Oa1's possible downstream G alpha partner (Gai3) the Oa1 pathway is becoming clearer and future of Oa1 research looks promising.[18]

Touloukian et al. have characterized OA1 immunologically as a melanoma/melanocyte differentiation antigen.[19] Flow cytometry data suggests that OA1-specific T cells are all CD8+. This indicates that OA1 peptide is processed and presented on the surface of melanoma cells to be recognized by antigen-specific T cells. Moreover, recognition of OA1 by T cells induces cytokine production by the OA1-specific T cells.This means that OA1 is a potential target for melanoma vaccines.

Molecular biology of Oa1

Human Oa1 gene has been identified by positional cloning as a 40kb gene mapped to Xp22.3-Xp22.2.[20][21] Later, a mouse homolog of the human Oa1 gene was also identified and cloned. It codes for a 404 amino acid long protein with up to three potential glycosylation sites. The transcript has been found to be expressing very well in retinal pigment epithelium and skin and to a much lesser extent in brain and adrenal glands.[22]

Mutations in Oa1 have been well characterized and studied using various techniques like southern blot analyses, single-strand conformation polymorphism and sequence analysis.[23] Most of these mutations have been reported to be occurring in the N-terminus and few in the trans-membrane regions but very rarely in the much conserved cytoplasmic C-terminus. Populations belonging to different ethnic groups have been extensively analyzed and a database has been created recording the details of mutations related to OA1.[24] A total of 25 missense, 2 nonsense, 9 frameshift, and 5 splicing mutations have been reported till date.[25] In addition to these mutations, there also occur several deletions in one or many of the exons of Oa1 gene, especially exon 2. These deletions are presumed to be because of unequal crossing-over due to the presence of flanking Alu regions. In some cases, the entire Oa1 gene is deleted along with other contiguous genes. Many different polymorphisms have also been detected, mainly in intron 1.[26]

Tissue-specific control of Oa1 transcription is by a 617bp long E-box region bound by Mitf.[27] Mitf has been shown to regulate expression of many melanosomal genes like TYR and TRP-1 through the E-box motif (CATGTG). Vetrini et al. have used adenoviral vectors to study tissue-specificity of Oa1 transcription through Mitf and observed that this regulation in conserved in human Oa1 gene.[28]

Structure of OA1 protein

Human Oa1 gene product was initially identified as a 60kDa protein formed from a 46-48kDa precursor.[29] The OA1 disease is due to defect in the OA1 receptor. This receptor has been shown to be similar to class C G- protein coupled receptors (GPCR). OA1 receptor has a characteristic GPCR structure-7 transmembrane helices with 3 cytoplasmic loops and 3 extracellular loops and an extracellular N- terminus and cytoplasmic C-terminus. Recently the ligand activating this receptor was found.[30] A recent computational work has provided some insight into the three-dimensional structure of this protein and its dynamic interactions with its known ligands.[31]

Localization of the OA1 protein

Shen, et al. created fusion proteins between OA1 and GFP.[32] Melanosomal localization of OA1 has been confirmed by immuno-electron microscopy and other techniques alike. Localization patterns of wild type OA1-GFP and mutated OA1-GFP were compared. The wild type OA1 localized to late endosomal or lysosomal compartments. This is supported by data from Samaraweera, et al. that OA1 colocalizes with Lamp1, which is a marker for late endosomal compartment. Hence, OA1 might traffick itself out of this compartment to the melanosomes.[33]

In addition to retina and melanoma, OA1 protein product was also detected in human pigment cells like melanosomal membrane glycoprotein.[34] This suggests that OA1 might be involved in melanosome biogenesis. Coimmunoprecipitation studies of OA1 with Gβ and Gαi in melanocyte extracts revealed its specific interaction with Gαi.[35] Further study have also shown that OA1 interact specifically with Gαi3 subtype.[36][37][38] Moreover, since OA1 is an organellar GPCR, it may represent an unidentified pathway in the melanosome. Until recently, it was believed that the probable ligand for OA1 might be within the melanosomal lumen, maybe one of the components of the melanogenic pathway since it is so closely related to melanosome biogenesis.[39] This has been proved now.[40]

Studies by Samaraweera, et al. revealed OA1 as an endolysosomal protein.[41] Schiaffino, et al. already proved that it is an integral membrane protein.[42] Newton et al. have shown that it has three probable glycosylation sites.[43] Furthermore, OA1 was found to be stimulated by α-melanocortin stimulating hormone but inhibited by agouti signal protein.[44] The fact that OA1 responds to melanin modifiers indicates its probable role in melanogenesis. Just like other melanosomal proteins TYR and TRP-1, processing of OA1 also occurs in the golgi.[45] Endogenous OA1 protein expressed by normal human melanocytes is detected as a 60kDa protein.

Receptor-Ligand interactions

Very recently the orphan OA1 receptor has been de-orphaned. Studies showed that L-DOPA is the specific ligand for the OA1 receptor.[46] L-DOPA is a by-product of melanin biosynthetic pathway. During melanin synthesis, L-DOPA is released to the retina in the retinal pigment epithelium and is necessary for specific stages of retinal development. Activation of the OA1 receptor by L-DOPA leads to the secretion of a neurotropic factor by the retinal pigment epithelium that helps in normal retinal development.[47]

Mutations

The OA1 mutants were classified into two major groups based on glycosylation and localization patterns. While group I consisted of normally glycosylated OA1, group II represented aberrantly glycosylated OA1 which is indistinguishable from the wild type.[48] However, both these studies revealed that in >60% of these mutations, the protein was retained in the ER and which is assumed to be the major cause of OA1. They also revealed that the protein levels decreased drastically, probably due to misfolding of the protein in the ER. Some of the mutations reported in second and third cytoplasmic loops (these regions are known to be critical for GPCR downstream signaling) are believed to affect transduction of the signals from OA1 via G proteins.[49][50]

Class Localization Mutations
I Endoplasmic reticulum : missense mutations in the N-terminus G35D, L39R
II LAMP2 positive granules and ER D78V, G84R, C116R, G118E, A173D, W292G
III Lysosomal compartment W133R, A138V, S152N, T232K, E235K

Functions of OA1

Though the exact role of OA1 is yet to be confirmed, many studies give clues about the probable roles of OA1. The Oa1 gene product might be involved in vesicular trafficking or sorting them to the melanosomes.[51] It is also believed to be involved in redistribution of mannose-6-phosphate receptors, thus suggesting that it is important for melanogensis.[52] Literature shows that it plays a major role in the final stages of growth and maturation of melanosomes. This conclusion is based on the fact that there are no intermediates of melanosome-melanosome fusion and the number of melanosomes decreases only on maturation of the cell and not in the initial stages of development. A number of genes in Drosophila, like the hook gene that alter ocular pigment granules have been shown to affect lysosomal delivery.[53] Moreover, it has been found that in normal conditions, melanosomal proteins traffic normally to late endosomes, while in the absence of OA1, they continue to accumulate in the mature melanosomes. This may mean that OA1 acts as a stop signal for melanosomal growth.[54]

External links

References

  1. ^ Oetting, W.S. (2002). New insights into ocular albinism type 1(OA1): Mutations and polymorphisms of the Oa1 gene. Human Mutations 19:85.
  2. ^ Incerti, B., Cortese, K., Pizzigoni, A., Surace, E.M., Varani, S., Coppola, M., Jeffery, G., Seeliger, M., Jaissle, G., Bennett, D.C., Marigo, V., Schiaffino, M.V., Tacchetti, C. and Ballabio, A. (2000). Oa1 knock-out: New insights on the pathogenesis of ocular albinism type 1. Human Molecular Genetics 9(19):2781.
  3. ^ Burns, W.N., Schiaffino, V.M. and Lewis, R.A. (1998). Repeated transmission of X-linked ocular albinism type 1 by a carrier oocyte donor. Fertility and Sterility 70(6):1169.
  4. ^ Carden, S.M., Boissy, R.E., Schoettker, P.J. and Good, W.V. (1998). Albinism: Modern molecular diagnosis. British Journal of Ophthalmology 82:189.
  5. ^ Shen, B., Samaraweera, P., Rosenberg, B. and Orlow, S.J. (2001). Ocular albinism 1: More than meets the eye. Pigment Cell Research 14:243.
  6. ^ Schiaffino, M.V., d'Addio, M., Alloni, A., Baschirotto, C., Valetti, C., Cortese, K., Puri, C., Bassi, M.T., Colla, C., De Luca, M., Tacchetti, C. and Ballabio, A. (1999). Ocular albinism: Evidence for a defect in an intracellular signal transduction system. Nature Genetics 23:108.
  7. ^ Kushimoto, T., Basrur, V., Valencia, J., Matsunaga, J., Viera, W.D., Ferrans, V.J., Muller, J., Appella, E. and Hearing, V.J. (2001). A model for melanosome biogenesis based on the purification and analysis of early melanosomes. Proceedings at the National Academy of Sciences 98(19):10698.
  8. ^ Incerti, B., Cortese, K., Pizzigoni, A., Surace, E.M., Varani, S., Coppola, M., Jeffery, G., Seeliger, M., Jaissle, G., Bennett, D.C., Marigo, V., Schiaffino, M.V., Tacchetti, C. and Ballabio, A. (2000). Oa1 knock-out: New insights on the pathogenesis of ocular albinism type 1. Human Molecular Genetics 9(19):2781.
  9. ^ Hegde, M., Lewis, R.A. and Richards, C.S. (2002). Diagnostic DNA testing for X-linked ocular albinism (OA1) with a hierarchical mutation screening protocol. Genetic Testing 6(1):7.
  10. ^ Kushimoto, T., Basrur, V., Valencia, J., Matsunaga, J., Viera, W.D., Ferrans, V.J., Muller, J., Appella, E. and Hearing, V.J. (2001). A model for melanosome biogenesis based on the purification and analysis of early melanosomes. Proceedings at the National Academy of Sciences 98(19):10698.
  11. ^ Kushimoto, T., Basrur, V., Valencia, J., Matsunaga, J., Viera, W.D., Ferrans, V.J., Muller, J., Appella, E. and Hearing, V.J. (2001). A model for melanosome biogenesis based on the purification and analysis of early melanosomes. Proceedings at the National Academy of Sciences 98(19):10698.
  12. ^ http://www.albinism.org/publications/ocular.html
  13. ^ Surace, E.M., Angeletti, B., Ballabio, A. and Marigo, V. (2000). Expression pattern of the ocular albinism type 1 (Oa1) gene in the murine retinal pigment epithelium. Investigative Ophthalmology and Visual Science 41(13):4333.
  14. ^ Lauronen, L., Jalkanen, R., Huttunen, J., Carlsson, E., Tuupanen, S., Lindh, S., Forsius, H., Sankila, E.M. and Alitalo, T. (2005). Abnormal crossing over of the optic fibres shown by evoked magnetic fields in patients with ocular albinism with a novel mutation in the OA1 gene. British Journal of Ophthalmology 89:820.
  15. ^ Oetting, W.S. and King, R. A.(1999). Molecular basis of albinism: Mutations and polymorphisms of pigmented genes associated with albinism. Human Mutations 13:99.
  16. ^ Incerti, B., Cortese, K., Pizzigoni, A., Surace, E.M., Varani, S., Coppola, M., Jeffery, G., Seeliger, M., Jaissle, G., Bennett, D.C., Marigo, V., Schiaffino, M.V., Tacchetti, C. and Ballabio, A. (2000). Oa1 knock-out: New insights on the pathogenesis of ocular albinism type 1. Human Molecular Genetics 9(19):2781.
  17. ^ http://www.albinism.org/publications/ocular.html
  18. ^ <37>(uncovering the OA1 signaling pathway, Lopez, V.M., Decatur, C.L., Stamer, W.D., Lynch, R.M. and McKay, B.S. (2008). L-DOPA is an endogenous ligand for OA1. PLoS Biology 6(9):e236.
  19. ^ Shen, B., Rosenberg, B. and Orlow, S.J. (2001). Intracellular distribution and late endosomal effects of the ocular albinism type 1 gene product: Consequences of disease-causing mutations and implications for melanosome biogenesis. Traffic 2:202.
  20. ^ Shen, B., Samaraweera, P., Rosenberg, B. and Orlow, S.J. (2001). Ocular albinism 1: More than meets the eye. Pigment Cell Research 14:243.
  21. ^ Oetting, W.S. and King, R. A.(1999). Molecular basis of albinism: Mutations and polymorphisms of pigmented genes associated with albinism. Human Mutations 13:99.
  22. ^ Oetting, W.S. and King, R. A.(1999). Molecular basis of albinism: Mutations and polymorphisms of pigmented genes associated with albinism. Human Mutations 13:99.
  23. ^ Hegde, M., Lewis, R.A. and Richards, C.S. (2002). Diagnostic DNA testing for X-linked ocular albinism (OA1) with a hierarchical mutation screening protocol. Genetic Testing 6(1):7.
  24. ^ http://www.cbc.umm.edu/tad
  25. ^ Oetting, W.S. and King, R. A.(1999). Molecular basis of albinism: Mutations and polymorphisms of pigmented genes associated with albinism. Human Mutations 13:99.
  26. ^ Oetting, W.S. and King, R. A.(1999). Molecular basis of albinism: Mutations and polymorphisms of pigmented genes associated with albinism. Human Mutations 13:99.
  27. ^ Vetrini, F., Auricchio, A., Du, J., Angeletti, B., Fisher, D.E., Ballabio, A. and Marigo, V. (2004). The microphthalmis transcription factor (Mitf) controls expression of the ocular albinism type 1 gene: Link between melanin synthesis and melanosome biogenesis. Molecular and Cellular Biology 24(15):6550.
  28. ^ Vetrini, F., Auricchio, A., Du, J., Angeletti, B., Fisher, D. E., Ballabio, A., Marigo, V. (2004). The microphthalmis transcription factor (Mitf) controls expression of the ocular albinism type 1 gene: link between melanin synthesis and melanosome biogenesis. Mol Cell Biol 24(15): 6550
  29. ^ Shen, B., Samaraweera, P., Rosenberg, B. and Orlow, S.J. (2001). Ocular albinism 1: More than meets the eye. Pigment Cell Research 14:243.
  30. ^ Lopez, V.M., Decatur, C.L., Stamer, W.D., Lynch, R.M. and McKay, B.S. (2008). L-DOPA is an endogenous ligand for OA1. PLoS Biology 6(9):e236.
  31. ^ Ghosh, A., Sonavane, U., Andhirka, S.K., Aradhyam, G.K., Joshi, R. (2012). Structural insights into human GPCR protein OA1: a computational perspective. Journal of Molecular Modeling 18(5):2117.
  32. ^ Shen, B., Samaraweera, P., Rosenberg, B. and Orlow, S.J. (2001). Ocular albinism 1: More than meets the eye. Pigment Cell Research 14:243.
  33. ^ Samaraweera, P., Shen, B., Newton, J.M., Barsh, G.S. and Orlow, S.J. (2001). The mouse ocular albinism 1 gene product is an endolysosomal protein. Experimental Eye Research 72:319.
  34. ^ Incerti, B., Cortese, K., Pizzigoni, A., Surace, E.M., Varani, S., Coppola, M., Jeffery, G., Seeliger, M., Jaissle, G., Bennett, D.C., Marigo, V., Schiaffino, M.V., Tacchetti, C. and Ballabio, A. (2000). Oa1 knock-out: New insights on the pathogenesis of ocular albinism type 1. Human Molecular Genetics 9(19):2781.
  35. ^ Oetting, W.S. (2002). New insights into ocular albinism type 1(OA1): Mutations and polymorphisms of the Oa1 gene. Human Mutations 19:85.
  36. ^ Young, Alejandra; Powelson, Elisabeth B.; Whitney, Irene E.; Raven, Mary A.; Nusinowitz, Steven; Jiang, Meisheng; Birnbaumer, Lutz; Reese, Benjamin E.; Farber, Debora B. (2008-07-01). "Involvement of OA1, an Intracellular GPCR, and Gαi3, Its Binding Protein, in Melanosomal Biogenesis and Optic Pathway Formation". Investigative ophthalmology & visual science. 49 (7): 3245–3252. doi:10.1167/iovs.08-1806. ISSN 0146-0404. PMC 2881626. PMID 18378571.
  37. ^ Young, Alejandra; Jiang, Meisheng; Wang, Ying; Ahmedli, Novruz B.; Ramirez, John; Reese, Benjamin E.; Birnbaumer, Lutz; Farber, Debora B. (2011-09-08). "Specific Interaction of Gαi3 with the Oa1 G-Protein Coupled Receptor Controls the Size and Density of Melanosomes in Retinal Pigment Epithelium". PLoS ONE. 6 (9): e24376. doi:10.1371/journal.pone.0024376. PMC 3169599. PMID 21931697.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  38. ^ Young, Alejandra; Wang, Ying; Ahmedli, Novruz B.; Jiang, Meisheng; Farber, Debora B. (2013-09-30). "A Constitutively Active Gαi3 Protein Corrects the Abnormal Retinal Pigment Epithelium Phenotype of Oa1−/− mice". PLoS ONE. 8 (9): e76240. doi:10.1371/journal.pone.0076240. PMC 3787026. PMID 24098784.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  39. ^ Incerti, B., Cortese, K., Pizzigoni, A., Surace, E.M., Varani, S., Coppola, M., Jeffery, G., Seeliger, M., Jaissle, G., Bennett, D.C., Marigo, V., Schiaffino, M.V., Tacchetti, C. and Ballabio, A. (2000). Oa1 knock-out: New insights on the pathogenesis of ocular albinism type 1. Human Molecular Genetics 9(19):2781.
  40. ^ Lopez, V.M., Decatur, C.L., Stamer, W.D., Lynch, R.M. and McKay, B.S. (2008). L-DOPA is an endogenous ligand for OA1. PLoS Biology 6(9):e236.
  41. ^ Samaraweera, P., Shen, B., Newton, J.M., Barsh, G.S. and Orlow, S.J. (2001). The mouse ocular albinism 1 gene product is an endolysosomal protein. Experimental Eye Research 72:319.
  42. ^ Schiaffino, M.V., d'Addio, M., Alloni, A., Baschirotto, C., Valetti, C., Cortese, K., Puri, C., Bassi, M.T., Colla, C., De Luca, M., Tacchetti, C. and Ballabio, A. (1999). Ocular albinism: Evidence for a defect in an intracellular signal transduction system. Nature Genetics 23:108.
  43. ^ Newton, J.M., Orlow, S.J. and Barsh, G.S. (1996). Isolation and characterization of a mouse homolog of the X-linked ocular albinism (OA1) gene. Genomics 37:219.
  44. ^ Samaraweera, P., Shen, B., Newton, J.M., Barsh, G.S. and Orlow, S.J. (2001). The mouse ocular albinism 1 gene product is an endolysosomal protein. Experimental Eye Research 72:319.
  45. ^ d'Addio, M., Pizzigoni, A., Bassi, M.T., Baschirotto, C., Valetti, C., Incerti, B., Clementi, M., De Luca, M., Ballabio, A. and Schiaffino, M.V. (2000). Defective intracellular transport and processing of OA1 is a major cause of ocular albinism type 1. Human Molecular Genetics 9(20):3011.
  46. ^ Gross, L. (2008). A molecular link between albinism and visual deficits. PLoS Biology 6(9):e248.
  47. ^ Lopez, V.M., Decatur, C.L., Stamer, W.D., Lynch, R.M. and McKay, B.S. (2008). L-DOPA is an endogenous ligand for OA1. PLoS Biology 6(9):e236.
  48. ^ Shen, B., Samaraweera, P., Rosenberg, B. and Orlow, S.J. (2001). Ocular albinism 1: More than meets the eye. Pigment Cell Research 14:243.
  49. ^ Shen, B., Samaraweera, P., Rosenberg, B. and Orlow, S.J. (2001). Ocular albinism 1: More than meets the eye. Pigment Cell Research 14:243.
  50. ^ d'Addio, M., Pizzigoni, A., Bassi, M.T., Baschirotto, C., Valetti, C., Incerti, B., Clementi, M., De Luca, M., Ballabio, A. and Schiaffino, M.V. (2000). Defective intracellular transport and processing of OA1 is a major cause of ocular albinism type 1. Human Molecular Genetics 9(20):3011.
  51. ^ Samaraweera, P., Shen, B., Newton, J.M., Barsh, G.S. and Orlow, S.J. (2001). The mouse ocular albinism 1 gene product is an endolysosomal protein. Experimental Eye Research 72:319.
  52. ^ Oetting, W.S. (2002). New insights into ocular albinism type 1(OA1): Mutations and polymorphisms of the Oa1 gene. Human Mutations 19:85.
  53. ^ Oetting, W.S. and King, R. A.(1999). Molecular basis of albinism: Mutations and polymorphisms of pigmented genes associated with albinism. Human Mutations 13:99.
  54. ^ Shen, B., Rosenberg, B., and Orlow, S.J. (2001). Intracellular distribution and late endosomal effects of the ocular albinism type 1 gene product: Consequences of disease-causing mutations and implications for melanosome biogenesis. Traffic 2:202.
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