Xeroderma pigmentosum

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Xeroderma pigmentosum
Xeroderma pigmentosum 02.jpg
An eight-year-old girl from Guatemala with xeroderma pigmentosum[1]
Classification and external resources
Specialty medical genetics
ICD-10 Q82.1
ICD-9-CM 757.33
OMIM 278700
DiseasesDB 14198
MedlinePlus 001467
eMedicine derm/462 neuro/399
Patient UK Xeroderma pigmentosum
MeSH D014983
GeneReviews
Orphanet 910
Child suffering from xeroderma pigmentosum in Rukum, Nepal
Xeroderma pigmentosum has an autosomal recessive pattern of inheritance.

Xeroderma pigmentosum (XP) is a rare autosomal recessive genetic disorder of DNA repair in which the ability to repair damage caused by ultraviolet (UV) light is deficient.[2]:574 In extreme cases, all exposure to sunlight must be forbidden, no matter how small; as such, individuals with the disease are often colloquially referred to as "Moon child".[3] Multiple basal cell carcinomas (basaliomas) and other skin malignancies frequently occur at a young age in those with XP; metastatic malignant melanoma and squamous cell carcinoma[4] are the two most common causes of death in XP victims. This disease is present in both genders and in all races, with an incidence of 1:250,000 in the United States.[5] XP is roughly six times more common in Japanese people[4] than in other groups.

Normally, damage to DNA in epidermal cells occurs during exposure to UV light. The absorption of the high-energy light leads to the formation of pyrimidine dimers, namely cyclobutane-pyrimidine dimers and pyrimidine-6-4-pyrimidone photoproducts. In a healthy, normal human being, the damage is first excised by endonucleases. DNA polymerase then repairs the missing sequence, and ligase "seals" the transaction. This process is known as nucleotide excision repair.

Symptoms[edit]

Symptoms include:

  • Severe sunburn when exposed to only small amounts of sunlight. These often occur during a child's first exposure to sunlight.
  • Development of many freckles at an early age
  • Rough-surfaced growths (solar keratoses), and skin cancers
  • Eyes that are painfully sensitive to the sun and may easily become irritated, bloodshot and clouded
  • Blistering or freckling on minimum sun exposure
  • Spider Veins
  • Limited growth of hair on chest and legs
  • Scaly skin
  • Dry skin
  • Irregular dark spots on the skin
  • Corneal ulcerations

Genetics[edit]

One of the most frequent defects in xeroderma pigmentosum is an autosomal recessive genetic defect in which nucleotide excision repair (NER) enzymes are mutated, leading to a reduction in or elimination of NER.[6] If left unchecked, damage caused by ultraviolet light can cause mutations in individual cell's DNA. The causes of the neurological abnormalities are poorly understood and are not connected with exposure to ultraviolet light. The most current theories suggest that oxidative DNA damage is generated during normal metabolism in the central nervous system, and that some types of this damage must be repaired by NER[7]

Since DNA repair is under genetic control, it can easily undergo mutations. Many genetic disorders such as xeroderma pigmentosum (XP; MIM 278700) are caused by mutations in genes that repair DNA.[7] If the gene was not repaired correctly it could cause xeroderma pigmentosum in individuals. The autosomal recessive disorder xeroderma pigmentosum or XP has a frequency of 1 in every 250,000 individuals of all races and ethnic groups.[8] Those affected with the autosomal recessive disorder XP are extremely sensitive to UV light produced by the sun and even with a short exposure to it causes dry, flaking skin and pigmented spots that can develop into skin cancer. Individuals with XP are about 1,000 times more likely to develop skin cancer than individuals without the disorder.

The molecular defects in XP cells result in a greatly elevated induction of mutations in sun-exposed skin of affected individuals. This increased mutation frequency probably accounts for the pigmentation changes and the skin cancers. Examination of mutations in the p53 gene in tumors from XP patients reveal p53 mutations characteristic of UV exposure in the majority of tumors[8] As with all genetic disorders, genetic counseling and psychological support is appropriate for the families, to discuss probability of occurrence in future pregnancies, feelings of isolation and concern about career prospects. Although there is no cure for xeroderma pigmentosum, the effects can be minimized by getting protection from the sunlight and if possible early removal of precancerous lesions. The most common fate for individuals with XP is early death from cancer because they need to take outstanding measures to protect themselves from the dangers of the UV light. But if there is an absence of neurological problems and the individual is always protected or away from sunlight, the prognosis is good.

Diagnosis[edit]

Types[edit]

There are seven complementation groups, plus one variant form:

Type Diseases Database OMIM Gene Locus Also known as / description
Type A, I, XPA 29877 278700 XPA 9q22.3 Xeroderma pigmentosum group A - the classical form of XP
Type B, II, XPB 29878 133510 XPB 2q21 Xeroderma pigmentosum group B
Type C, III, XPC 29879 278720 XPC 3p25 Xeroderma pigmentosum group C
Type D, IV, XPD 29880 278730 278800 XPD ERCC6 19q13.2-q13.3, 10q11 Xeroderma pigmentosum group D or De Sanctis-Cacchione syndrome (can be considered a subtype of XPD)
Type E, V, XPE 29881 278740 DDB2 11p12-p11 Xeroderma pigmentosum group E
Type F, VI, XPF 29882 278760 ERCC4 16p13.3-p13.13 Xeroderma pigmentosum group F
Type G, VII, XPG 29883 278780 133530 RAD2 ERCC5 13q33 Xeroderma pigmentosum group G and COFS syndrome type 3
Type V, XPV 278750 POLH 6p21.1-p12 Xeroderma pigmentosum variant - these patients suffer from mutation in a gene that codes for a specialized DNA polymerase called polymerase-η (eta). Polymerase-η can replicate over the damage and is needed when cells enter S-phase in the presence of a DNA-replication.

Treatment[edit]

The most obvious, and often important part of treatment, is avoiding exposure to sunlight. This includes wearing protective clothing and using sunscreen (physical and chemical).[9] Keratosis can also be treated using cryotherapy or fluorouracil.[1] theoretically, the condition could be completely reversed if correct non-mutated endonuclease genes could be inserted into every cell into the body, and the most promising method to do this would be crispr. However, every cell in the body would have to be penetrated for a total cure, because the skin Does not protect against other forms of radiation, like x-rays, even at low quantities harmless for those without xeroderma pigmentosa.

Prognosis[edit]

Fewer than 40% of individuals with the disease survive beyond the age of 20. Some XP victims with less severe cases do manage to live well into their 40s.

Functions of XP repair proteins[edit]

The XPA protein acts during NER as a scaffold for assembly of other DNA repair proteins at sites of DNA damage to ensure appropriate excision of the damage.[10]

The XPB(ERCC3) protein is employed in unwinding the DNA double helix after DNA damage is initially recognized. Mutations in the XPB(ERCC3) gene can lead to XP or XP combined with Cockayne syndrome.[11]

The XPC protein forms a complex with RAD23B protein to form the initial damage recognition factor in global genomic nucleotide excision repair (GG-NER).[12] This complex recognizes a wide variety of damages that thermodynamically destabilize DNA duplexes.

The XPD(ERCC2) protein, in combination with the XPB helicase-containing transcription/repair complex TFIIH, is employed in unwinding the DNA duplex after damage is initially recognized. Mutations in the XPD(ERCC2) gene cause a variety of syndromes; XP, trichothiodystrophy (TTD), or a combination of XP and Cockayne syndrome (XPCS).[13][14] Both trichothiodystrophy and Cockayne syndrome display features of premature aging, suggesting an association between deficient DNA repair and premature aging (see DNA damage theory of aging).

XPE is a heterodimeric protein composed of two subunits. The larger subunit DDB1 primarily functions as a core component of CUL4A- and CUL4B-based E3 ubiquitin ligase complexes. Substrates that are ubiquitinnated by these complexes include proteins employed in DNA repair.[15]

The XPF(ERCC4) protein together with the ERCC1 protein forms a complex usually designated ERCC1-XPF. This complex separates the DNA helix for a short distance on either side of the site of damage. It then acts as a endonuclease to incise the damaged DNA strand on the 5’ side of the damaged site.[16] Mutant cells with deficient ERCC1-XPF are not only defective in NER, but also in the repair of double-strand breaks and inter-strand crosslinks.

The XPG protein is an endonuclease that incises DNA during NER at the 3’ side of the damaged nucleotide. Mutations in the XPG(ERCC5) gene can lead to XP alone, or in combination with Cockayne syndrome (CS), or in combination with infantile lethal cerebro-oculo-facio-skeletal syndrome.[17]

In popular culture[edit]

These fictional characters have XP:

  • In 1999 the series Ace Combat presented a character named Rena Hirose that suffered a similar form of XP (Silverstone)
  • Christopher Snow in Dean Koontz's Moonlight Bay Trilogy
  • 1994 CBS-TV movie Children of the Dark is based on XP.
  • Luke in the 2002 novel Going Out by Scarlett Thomas
  • In the Channel 4 series Ultraviolet, one of the humans is mistaken for a vampire because he avoids sunlight, when in fact he has XP.
  • In the book The Lucifer Code (originally published in 1997 as "Lucifer") the character Bradley Soames suffers from XP, and wears an all-encompassing "suit" complete with mask, hood and heavily tinted lenses in order to venture outdoors.
  • In the independent film Dark Side of the Sun (1988) with Brad Pitt as the main character suffering from XP.
  • In the 2001 film The Others, the two children, Anne and Nicholas, suffer from XP.
  • In the 2003 novel Second Glance by Jodi Picoult, Ethan Wakeman, the 9-year-old nephew of Ross Wakeman (the main protagonist) has XP.
  • The 2003 Angela Johnson novel, A Cool Moonlight, centers on a girl who has XP and can never be in the sun. The family has gone to drastic measures to help make her life easier, and to make her feel like a normal 8-year-old.
  • The 2006 Japanese drama "Taiyou no uta" (A Song to the Sun) centers around a girl with XP who dreams of being a singer.
  • The 2006 German film Mondscheinkinder (Children of the Moonlight) features 12-year-old Lisa who creates a fantasy world for her 6-year-old brother Paul, who has XP and cannot leave the house. Their special relationship is threatened when Lisa gets her first boyfriend, facing her with hard choices.[18]
  • The Spanish film "Eskalofrío" or "Shiver" released in 2008 featured a main character named Santi who is ostracized as he suffers from the condition.
  • The 2011 film La permission de minuit by French director Delphine Gleize centers on a teenage boy with XP.
  • The 2012 documentary "Sun Kissed" explores the XP problem on the Navajo Indian Reservation.
  • The 2013 young adult novel What We Saw at Night by Jacquelyn Mitchard tells the story of three teenagers who are suffering from this disease, go out only when dark and witness something strange one night.
  • The 2013 middle grade novel "Doom & Gloom" by M. J. Shaughnessy tells the story of a twelve-year-old boy who triumphs over his disease by donning a protective solar suit and becoming a superhero.
  • The 2014 adult fiction book The Deepest Secret by Carla Buckley tells the story of a mother with a son who has XP and the lengths she will go to in order to protect him from a crisis that threatens to tear the community apart.[19]
  • In the 2016 horror film Lights Out, the villain, Diana had this condition. She was killed when the doctors at the mental institution she and Sophie stayed at tried treating the condition, but it went awry.

In the 2017 Marvel blockbuster "Logan", the conclusion to Hugh Jackman's performance as Wolverine, the character Caliban exhibits symptoms of XP upon torture by the Reavers, thus explaining the usage in the movie of the saying, "Beware of the light."

  • March 28, 2017 episode of Criminal Minds "Hell's Kitchen - the main protagonist suffers from XP and believes blood of victims will cure him

See also[edit]

References[edit]

  1. ^ a b Halpern, J.; Hopping, B.; Brostoff, J. (2008). "Photosensitivity, corneal scarring and developmental delay: Xeroderma Pigmentosum in a tropical country". Cases journal. 1 (1): 254. PMC 2577106Freely accessible. PMID 18937855. doi:10.1186/1757-1626-1-254. 
  2. ^ James, William; Berger, Timothy; Elston, Dirk (2005). Andrews' Diseases of the Skin: Clinical Dermatology. (10th ed.). Saunders. ISBN 0-7216-2921-0.
  3. ^ Medical Biochemistry at a Glance. John Wiley & Sons. 28 November 2011. ISBN 1118292405. Retrieved 17 June 2011. Xeroderma pigmentosa is a rare, autosomal recessive disease caused by a defective UV-specific endonuclease. Patients with mutations are unable to repair DNA damage caused by sunlight and have been described as "children of the night." 
  4. ^ a b Li, Lei (January 8, 2007). "Chapter 3 Nucleotide Excision Repair". DNA REPAIR, GENETIC INSTABILITY, AND CANCER. World Scientific Publishing. pp. 75–76. ISBN 981-270-014-5. 
  5. ^ Lehmann AR, McGibbon D, Stefanini M (2011). "Xeroderma pigmentosum". Orphanet J Rare Dis. 6: 70. PMC 3221642Freely accessible. PMID 22044607. doi:10.1186/1750-1172-6-70. 
  6. ^ E. C. Friedberg; G. C. Walker; W. Siede; R. D. Wood; R. A. Schultz; T. Ellenberger (2006). DNA repair and mutagenesis. Washington: ASM Press. p. 1118. ISBN 978-1-55581-319-2. 
  7. ^ a b Brooks PJ DNA Repair (Amst). 2014 March 2; 7(7):1168-79.
  8. ^ a b Daya-Grosjean L, Sarasin A Mutat Res. 2014 March 2; 571(1-2):43-56
  9. ^ Nussbaum, Robert; McInnes, Roderick; Willard, Huntington. Genetics in Medicine. Elsevier. ISBN 978-14377-0696-3. 
  10. ^ Sugitani N, Sivley RM, Perry KE, Capra JA, Chazin WJ (2016). "XPA: A key scaffold for human nucleotide excision repair". DNA Repair (Amst.). 44: 123–35. PMID 27247238. doi:10.1016/j.dnarep.2016.05.018. 
  11. ^ Oh KS, Khan SG, Jaspers NG, Raams A, Ueda T, Lehmann A, Friedmann PS, Emmert S, Gratchev A, Lachlan K, Lucassan A, Baker CC, Kraemer KH (2006). "Phenotypic heterogeneity in the XPB DNA helicase gene (ERCC3): xeroderma pigmentosum without and with Cockayne syndrome". Hum. Mutat. 27 (11): 1092–103. PMID 16947863. doi:10.1002/humu.20392. 
  12. ^ Sugasawa K, Ng JM, Masutani C, Iwai S, van der Spek PJ, Eker AP, Hanaoka F, Bootsma D, Hoeijmakers JH (1998). "Xeroderma pigmentosum group C protein complex is the initiator of global genome nucleotide excision repair". Mol. Cell. 2 (2): 223–32. PMID 9734359. 
  13. ^ Andressoo JO, Hoeijmakers JH, Mitchell JR (2006). "Nucleotide excision repair disorders and the balance between cancer and aging". Cell Cycle. 5 (24): 2886–8. PMID 17172862. doi:10.4161/cc.5.24.3565. 
  14. ^ van de Ven M, Andressoo JO, van der Horst GT, Hoeijmakers JH, Mitchell JR (2012). "Effects of compound heterozygosity at the Xpd locus on cancer and ageing in mouse models". DNA Repair (Amst.). 11 (11): 874–83. PMID 23046824. doi:10.1016/j.dnarep.2012.08.003. 
  15. ^ Iovine B, Iannella ML, Bevilacqua MA (2011). "Damage-specific DNA binding protein 1 (DDB1): a protein with a wide range of functions". Int. J. Biochem. Cell Biol. 43 (12): 1664–7. PMID 21959250. doi:10.1016/j.biocel.2011.09.001. 
  16. ^ Sijbers AM, de Laat WL, Ariza RR, Biggerstaff M, Wei YF, Moggs JG, Carter KC, Shell BK, Evans E, de Jong MC, Rademakers S, de Rooij J, Jaspers NG, Hoeijmakers JH, Wood RD (1996). "Xeroderma pigmentosum group F caused by a defect in a structure-specific DNA repair endonuclease". Cell. 86 (5): 811–22. PMID 8797827. 
  17. ^ Barnhoorn S, Uittenboogaard LM, Jaarsma D, Vermeij WP, Tresini M, Weymaere M, Menoni H, Brandt RM, de Waard MC, Botter SM, Sarker AH, Jaspers NG, van der Horst GT, Cooper PK, Hoeijmakers JH, van der Pluijm I (2014). "Cell-autonomous progeroid changes in conditional mouse models for repair endonuclease XPG deficiency". PLoS Genet. 10 (10): e1004686. PMC 4191938Freely accessible. PMID 25299392. doi:10.1371/journal.pgen.1004686. 
  18. ^ See the website of the movie, in German: http://www.mondscheinkinder-der-film.de/
  19. ^ https://www.goodreads.com/book/show/18248415-the-deepest-secret?ac=1

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