Microphthalmia‐Associated Transcription Factor (MITF) Locus Lacks Linkage To Human Vitiligo Or Osteopetrosis: An Evaluation

Abstract

The microphthalmia-associated transcription factor (MITF) locus has been mapped to human chromosome 3p12-p14.1, and encodes a basic helix-loop-helix zipper (bHLH-ZIP) protein homologous to a number of transcription factors. Numerous mutations at the mouse microphthalmia (mi) locus have been described, and all have reduced or absent pigmentation of the eyes, ears, and/or pelage, with some genotypes exhibiting small or absent eyes and osteopetrosis. The mivit/vit mutation at the mouse mi locus produces a postnatal depigmentation that resembles human vitiligo. The mice homozygous for this mi allele show a progressive loss of cutaneous, hair and ocular pigmentation with age. Vitiligo, an acquired depigmentary disorder, is characterized by patchy depigmentation of skin that generally begins around puberty and tends to become more progressive over time. There is suggestive evidence that human vitiligo may be inherited; however, the mode of inheritance is still debated and the pathogenesis is not clearly delineated. The human disorder osteopetrosis is characterized by a generalized net accumulation of skeletal mass and results from reduced osteoclast function in the bone. This is an inherited disorder and has been associated with mi in a mutant mouse. Therefore, the possible involvement of the MITF locus in the pathogenesis of either familial vitiligo or osteopetrosis was investigated. Linkage analysis was performed using microsatellite polymorphic markers D3S2465, D3S1261, and D3S1766 on genomic DNA from 26 families with vitiligo/osteopetrosis. D3S1261 is physically located at or near the MITF locus, while D3S2465 and D3S1766 are flanking the locus at about 17.5 cM genetic distance each side. Evidence from LOD score analysis surprisingly indicated that none of the families with vitiligo or osteopetrosis are linked to these short tandem repeat polymorphisms (STRPs). Thus, the human homolog (MITF) of the mouse mi gene, a good candidate gene at the phenotypic level, may not be involved in the pathogenesis of familial human vitiligo or osteopetrosis.

Senile hair graying: H 2 O 2 ‐mediated oxidative stress affects human hair color by blunting methionine sulfoxide repair

“…Free l-Met is an efficient H 2 O 2 scavenger due to formation of free Met-SϭO over the proteinbound Met-SϭO formation, if the concentrations are sufficiently high. This result underlines once more the importance of Met 374 in the enzyme active site (29,(31)(32)(33).…”

The genetics of generalized vitiligo and associated autoimmune diseases

“…The first vitiligo linkage data were negative, showing lack of apparent linkage to a single candidate gene tested, MITF [55]. The first positive linkage data were indirect, showing linkage between a locus on chromosome 17p13, called SLEV1, and systemic lupus erythematosus in families that included at least one patient with vitiligo [56].…”

A Role for Tyrosinase-Related Protein 1 in 4-tert-Butylphenol-Induced Toxicity in Melanocytes

“…21 The first mouse model for vitiligo was an Mitf mutant 41 ; however, mutations at the MITF locus do not result in human vitiligo. 42 We therefore propose that disruption of the pathway/s that regulate MITF expression and/or pathways regulated by MITF itself play a role in the etiology of this condition. Disruption Figure 8.…”