Promoter polymorphism -119C/G in MYG1 (C12orf10) gene is related to vitiligo susceptibility and Arg4Gln affects mitochondrial entrance of Myg1

Abstract

BackgroundMYG1 (Melanocyte proliferating gene 1, also C12orf10 in human) is a ubiquitous nucleo-mitochondrial protein, involved in early developmental processes and in adult stress/illness conditions. We recently showed that MYG1 mRNA expression is elevated in the skin of vitiligo patients. Our aim was to examine nine known polymorphisms in the MYG1 gene, to investigate their functionality, and to study their association with vitiligo susceptibility.MethodsNine single nucleotide polymorphisms (SNPs) in the MYG1 locus were investigated by SNPlex assay and/or sequencing in vitiligo patients (n = 124) and controls (n = 325). MYG1 expression in skin biopsies was detected by quantitative-real time PCR (Q-RT-PCR) and polymorphisms were further analysed using luciferase and YFP reporters in the cell culture.ResultsControl subjects with -119G promoter allele (rs1465073) exhibited significantly higher MYG1 mRNA levels than controls with -119C allele (P = 0.01). Higher activity of -119G promoter was confirmed by luciferase assay. Single marker association analysis showed that the -119G allele was more frequent in vitiligo patients (47.1%) compared to controls (39.3%, P < 0.05, OR 1.37, 95%CI 1.02-1.85). Analysis based on the stage of progression of the vitiligo revealed that the increased frequency of -119G allele occurred prevalently in the group of patients with active vitiligo (n = 86) compared to the control group (48.2% versus 39.3%, P < 0.05; OR 1.44, 95%CI 1.02-2.03). Additionally, we showed that glutamine in the fourth position (in Arg4Gln polymorphism) completely eliminated mitochondrial entrance of YFP-tagged Myg1 protein in cell culture. The analysis of available EST, cDNA and genomic DNA sequences revealed that Myg1 4Gln allele is remarkably present in human populations but is never detected in homozygous state according to the HapMap database.ConclusionsOur study demonstrated that both MYG1 promoter polymorphism -119C/G and Arg4Gln polymorphism in the mitochondrial signal of Myg1 have a functional impact on the regulation of the MYG1 gene and promoter polymorphism (-119C/G) is related with suspectibility for actively progressing vitiligo.

Correlation of increased MYG1 expression and its promoter polymorphism with disease progression and higher susceptibility in vitiligo patients

“…In the present study, -119G allele was prevalent in vitiligo patients as compared to controls and our results are in line with those of Philips et al [18]. Particularly active cases of vitiligo showed increased frequencies of -119G allele as compared to stable cases suggesting the crucial role of -119G allele in progression of the disease.…”

“…In addition, MYG1 has been found to be consistently up-regulated in skin biopsies from patients with atopic eczema [17]. Philips et al [18] demonstrated that both -119C/G promoter, and Arg4Gln polymorphisms in the mitochondrial signal of MYG1 have a functional impact on the regulation of the MYG1 gene. Previously, MYG1 promoter polymorphism (-119C/G) was shown to be associated with susceptibility for actively progressing vitiligo in Caucasian population.…”

Shared Genetic Relationships Underlying Generalized Vitiligo and Autoimmune Thyroid Disease

“…Similarly, MYG1 is a widely expressed gene shown on the basis of differential hybridization to have elevated expression in melanocytes from vitiligo patients (50). Variation in MYG1 has been found to affect levels of gene expression and to be marginally associated with active vitiligo (51), although this study did not apply appropriate correction for extensive multiple testing. A recent more global analysis of 16,000 transcripts in melanocytes cultured from vitiligo patients versus controls identified a list of 859 differentially expressed genes (52).…”

The Pathogenesis of Vitiligo

“…In active vitiligo patients, MYG1 expression was increased in both lesional and non-lesional skin, and within the lesional skin of non-active vitiligo patients. These results taken together thus suggests that the -119G allele of the MYG1 promoter sequence is a potential risk-allele for developing vitiligo and for the active state of the disease (Philips et al, 2010).…”

“…Kingo et al (2006) have demonstrated that messenger ribonucleic acid (mRNA) expression of melanocyte proliferating gene 1, or MYG1 (a gene involved in early developmental processes), is elevated in lesional skin of vitiligo patients. Nine SNPs are found within the MYG1 locus for susceptibility to vitiligo (Philips et al, 2010). The MYG1 gene consists of seven exons, culminating as 7.5 kilo-base pair (kb) of DNA on chromosome 12.…”