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LETTER TO EDITOR
Year : 2004  |  Volume : 70  |  Issue : 3  |  Page : 184-185

VIT1 gene and vitiligo


Sri Ramachandra Medical College and Research Institute (DU), Porur, Chennai, India

Correspondence Address:
Dept. of Dermatology and Venereology, Sri Ramachandra Medical College and Research Institute (DU), Porur, Chennai - 116, India
beapen@emirates.net.ae



How to cite this article:
Eapen BR. VIT1 gene and vitiligo. Indian J Dermatol Venereol Leprol 2004;70:184-5


How to cite this URL:
Eapen BR. VIT1 gene and vitiligo. Indian J Dermatol Venereol Leprol [serial online] 2004 [cited 2017 May 26];70:184-5. Available from: http://www.ijdvl.com/text.asp?2004/70/3/184/11101


Sir,
Though extensively studied, the pathophysiology of vitiligo remains an enigma. The striking features of vitiligo, which have to be explained by any hypothesis on its pathogenesis, include its apparent heritability, absence of melanocytes without obvious signs of inflammation, association with ocular abnormalities[1] and systemic disorders like thyroid disease, association with stress and trauma[2] and segmental distribution in a few cases.

A newly identified gene called VIT1[3] was found to be associated with vitiligo. A detailed study of the structure of this gene using computational methods revealed features that could explain many of the distinctive features of vitiligo.

The VIT1 gene is located on chromosome 2p16. It has a refseq accession number of NM_018693 and the corresponding protein has an accession number of NP_061163. The genome has four exons and an overlapping region with the tumor marker MSH6. The protein had a single domain, a putative zinc finger in the N-recognin (ZnF-UBR1) with a Pfam accession number 02207 and smart00396.

N-recognin is an ubiquitin-protein ligase, the vital part of the N-end rule pathway.[4] The N-end rule pathway is the main initiator of cellular apoptosis by destruction of specific proteins. It has various isoforms recognizing various N-terminal amino acid sequences; hence the name N-end rule pathway. The presence of this ubiquitin domain on vitiligo-associated gene can explain many of the features described above. Ubiquitin expressed by VIT1 may be targeting any of the specific proteins expressed by melanocytes or those responsible for melanocyte activation, thereby leading to melanocyte apoptosis without significant inflammation. Both stress and trauma are known to increase ubiquitin production and worsen vitiligo. Steroids are known to inhibit certain types of cellular apoptosis, especially TNF-a induced apoptosis. This could explain the therapeutic utility of steroids in vitiligo.

Yet another protein sharing the same domain is retinoblastoma-associated factor. This may be a significant finding considering the fact that retinal pigmentary abnormalities are sometimes seen in vitiligo.

The significance of the overlap of VIT1 gene with MSH6 is not known. MSH6 is involved in mismatch repair and mutation in this region leads to various colorectal tumors.[5] Pigmentary changes are common in various intestinal polyposis syndromes, and the role of MSH6 remains to be explored.

Hence, genomic evidence suggests a ubiquitin mediated melanocyte specific apoptosis as a possible pathogenic mechanism in vitiligo. Histopathological evidence of inflammation in the normal-appearing skin adjacent to vitiliginous areas may be secondary to the cell injury. However, further research is required to find the probable target protein of this 'vitiligo associated ubiquitin'. This could have therapeutic applications as synthetic proteins with the same N-terminal sequence can act as a competitive inhibitor of this enzyme. 

   References Top

1.Cowan CL Jr, Halder RM, Grimes PE, Chakrabarti SG, Kenney JA Jr. Ocular disturbances in vitiligo. J Am Acad Dermatol 1986;15:17-24.  Back to cited text no. 1  [PUBMED]  
2.Porter JR, Beuf AH, Lerner A, Nordlund J. Psychosocial effect of vitiligo: A comparison of vitiligo patients with "normal" control subjects, with psoriasis patients, and with patients with other pigmentary disorders. J Am Acad Dermatol 1986;15:220-4.  Back to cited text no. 2  [PUBMED]  
3.Le Poole IC, Sarangarajan R, Zhao Y, Stennett LS, Brown TL, Sheth P, et al. 'VIT1', a novel gene associated with vitiligo. Pigment Cell Res 2001;14:475-84.  Back to cited text no. 3  [PUBMED]  [FULLTEXT]
4.Siepmann TJ, Bohnsack RN, Tokgoz Z, Baboshina OV, Haas AL. Protein interactions within the N-end rule ubiquitin ligation pathway. J Biol Chem 2003;278:9448-57.  Back to cited text no. 4  [PUBMED]  [FULLTEXT]
5.Hendriks Y, Franken P, Dierssen JW, De Leeuw W, Wijnen J, Dreef E, et al. Conventional and tissue microarray immuno-histochemical expression analysis of mismatch repair in hereditary colorectal tumors. Am J Pathol 2003;162:469-77.  Back to cited text no. 5  [PUBMED]  [FULLTEXT]

 

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