TTC7A

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TTC7A
Identifiers
Aliases TTC7A, MINAT, TTC7, GIDID, tetratricopeptide repeat domain 7A
External IDs MGI: 1920999 HomoloGene: 12515 GeneCards: TTC7A
Gene location (Human)
Chromosome 2 (human)
Chr. Chromosome 2 (human)[1]
Chromosome 2 (human)
Genomic location for TTC7A
Genomic location for TTC7A
Band 2p21 Start 46,916,157 bp[1]
End 47,076,137 bp[1]
Orthologs
Species Human Mouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_001288951
NM_001288953
NM_001288955
NM_020458

NM_028639

RefSeq (protein)

NP_001275880
NP_001275882
NP_001275884
NP_065191

NP_082915

Location (UCSC) Chr 2: 46.92 – 47.08 Mb Chr 17: 87.28 – 87.38 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Tetratricopeptide repeat domain 7A (TTC7A) is a protein that in humans is encoded by the TTC7A gene.[5]

Function[edit]

TPR domain-containing proteins, such as TTC7A, have diverse functions in cell cycle control, protein transport, phosphate turnover, and protein trafficking or secretion, and they can act as chaperones or scaffolding proteins.

Clinical significance[edit]

TTC7A deficiency is extremely rare with less than 30 cases reported to date.[citation needed] TTC7A deficiency disrupts epithelial intestinal cell growth thereby promoting multiple intestinal atresia (MIA), a rare type of bowel obstruction.[6] Not all patients with TTC7A Deficiency exhibit the same symptoms. Although quality of life is generally very poor for most children with very few surviving beyond the first year or two of life,[7] there is a broad spectrum of severity of symptoms varying from individual to individual with some forms of TTC7A Deficiency being less severe with survival being many years or even decades.

Mutations in this gene are known to cause hereditary multiple intestinal atresia (MIA), severe infantile or very early onset inflammatory bowel disease, extensive enteropathy, combined immunodeficiencies (CID), thyroid dysfunction, and alopecia.[8][9][10][11] Some TTC7A Deficiency patients have also been shown to develop lung disease [12][13][14]

There is no standard treatment for TTC7A Deficiency at this time. Management of TTC7A deficiency currently entails bowel resection for any atresias, possibly hematopoietic stem cell transplantation to correct the immunodeficiencies, and immunosuppression to help alleviate bowel disease and immune disregulation. Hematopoietic stem cell transplantation may be ineffective.[15]Small bowel transplant has proven successful in at least one case.[16]

Effect on Rho kinase activity[edit]

Research indicates that TTC7A deficiency results in "increased Rho kinase activity which disrupts polarity, growth, and differentiation of intestinal epithelial cells, and which impairs immune cell homeostasis, thereby promoting MIA-CID development." [17] Based on this research, it has been proposed that Rho kinase inhibitors may be a therapeutic option, although no specific rho kinase inhibitors are currently available for patient use with the exception of Fasudil which is only available in Japan. It has been shown that statins such as Lipitor are useful as Rho kinase inhibitors.[18] Therefore, statins may be helpful for the treatment of TTC7A deficiency, although this has yet to be proven.

References[edit]

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000068724 - Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000036918 - Ensembl, May 2017
  3. ^ "Human PubMed Reference:". 
  4. ^ "Mouse PubMed Reference:". 
  5. ^ "Entrez Gene: Tetratricopeptide repeat domain 7A". 
  6. ^ Bigorgne AE, Farin HF, Lemoine R, Mahlaoui N, Lambert N, Gil M, Schulz A, Philippet P, Schlesser P, Abrahamsen TG, Oymar K, Davies EG, Ellingsen CL, Leteurtre E, Moreau-Massart B, Berrebi D, Bole-Feysot C, Nischke P, Brousse N, Fischer A, Clevers H, de Saint Basile G (Jan 2014). "TTC7A mutations disrupt intestinal epithelial apicobasal polarity". The Journal of Clinical Investigation. 124 (1): 328–37. doi:10.1172/JCI71471. PMC 3871247Freely accessible. PMID 24292712. 
  7. ^ Notarangelo LD (2014). "Multiple intestinal atresia with combined immune deficiency". Curr. Opin. Pediatr. 26 (6): 690–6. doi:10.1097/MOP.0000000000000159. PMID 25268403. 
  8. ^ Chen R, Giliani S, Lanzi G, Mias GI, Lonardi S, Dobbs K, et al. (2013). "Whole-exome sequencing identifies tetratricopeptide repeat domain 7A (TTC7A) mutations for combined immunodeficiency with intestinal atresias". J. Allergy Clin. Immunol. 132 (3): 656–664.e17. doi:10.1016/j.jaci.2013.06.013. PMC 3759618Freely accessible. PMID 23830146. 
  9. ^ Samuels ME, Majewski J, Alirezaie N, Fernandez I, Casals F, Patey N, et al. (2013). "Exome sequencing identifies mutations in the gene TTC7A in French-Canadian cases with hereditary multiple intestinal atresia". J. Med. Genet. 50 (5): 324–9. doi:10.1136/jmedgenet-2012-101483. PMC 3625823Freely accessible. PMID 23423984. 
  10. ^ Avitzur Y, Guo C, Mastropaolo LA, Bahrami E, Chen H, Zhao Z, et al. (2014). "Mutations in tetratricopeptide repeat domain 7A result in a severe form of very early onset inflammatory bowel disease". Gastroenterology. 146 (4): 1028–39. doi:10.1053/j.gastro.2014.01.015. PMC 4002656Freely accessible. PMID 24417819. 
  11. ^ Lemoine R, Pachlopnik-Schmid J, Farin HF, Bigorgne A, Debré M, Sepulveda F, Héritier S, Lemale J, Talbotec C, Rieux-Laucat F, Ruemmele F, Morali A, Cathebras P, Nitschke P, Bole-Feysot C, Blanche S, Brousse N, Picard C, Clevers H, Fischer A, de Saint Basile G (2014). "Immune deficiency-related enteropathy-lymphocytopenia-alopecia syndrome results from tetratricopeptide repeat domain 7A deficiency". The Journal of Allergy and Clinical Immunology. 134 (6): 1354–1364.e6. doi:10.1016/j.jaci.2014.07.019. PMID 25174867. 
  12. ^ Ngan, Bo (May 2014). "Mutations in tetratricopeptide repeat domain 7A (TTC7A) are associated with combined immunodeficiency with dendriform lung ossification but no intestinal atresia". LymphoSign Journal. 1 (1). 
  13. ^ Fernandez I, Patey N, Marchand V, Birlea M, Maranda B, Haddad E, Decaluwe H, Le Deist F (Dec 2014). "Multiple intestinal atresia with combined immune deficiency related to TTC7A defect is a multiorgan pathology: study of a French-Canadian-based cohort". Medicine. 93 (29): e327. doi:10.1097/MD.0000000000000327. PMC 4602622Freely accessible. PMID 25546680. 
  14. ^ Agarwal NS, Northrop L, Anyane-Yeboa K, Aggarwal VS, Nagy PL, Demirdag YY (2014). "Tetratricopeptide repeat domain 7A (TTC7A) mutation in a newborn with multiple intestinal atresia and combined immunodeficiency". Journal of Clinical Immunology. 34 (6): 607–10. doi:10.1007/s10875-014-0067-7. PMID 24931897. 
  15. ^ http://www.bloodjournal.org/content/early/2016/07/14/blood-2016-01-696385?sso-checked=true
  16. ^ Gilroy RK, Coccia PF, Talmadge JE, Hatcher LI, Pirruccello SJ, Shaw BW, Rubocki RJ, Sudan DL, Langnas AN, Horslen SP (Feb 2004). "Donor immune reconstitution after liver-small bowel transplantation for multiple intestinal atresia with immunodeficiency". Blood. 103 (3): 1171–4. doi:10.1182/blood-2003-04-1187. PMID 14525785. 
  17. ^ "TTC7A mutations disrupt intestinal epithelial apicobasal polarity". www.jci.org. 2014-01-02. doi:10.1172/JCI71471. PMC 3871247Freely accessible. PMID 24292712. Retrieved 2015-10-20. 
  18. ^ Rentala, Satyanarayana; Chintala, Ramakrishna; Guda, Manohar; Chintala, Madhuri; Komarraju, Aruna Lakshmi; Mangamoori, Lakshmi Narasu (2013-11-22). "Atorvastatin inhibited Rho-associated kinase 1 (ROCK1) and focal adhesion kinase (FAK) mediated adhesion and differentiation of CD133+CD44+ prostate cancer stem cells". Biochemical and Biophysical Research Communications. 441 (3): 586–592. doi:10.1016/j.bbrc.2013.10.112. ISSN 1090-2104. PMID 24177008. 

External links[edit]