Candidate Gene Study Among Suscceptability Loci AIS4 In Chinese Patients With Vitiligo

Background Vitiligo vulgaris (MIM193200) is an acquired, non-contagious disorder in which progressive loss of viable melanocytes results in patchy pigmentation in the skin, hair, and oral mucosa. It can afflict all populations worldwide, with diverse prevalence rates ranging from 0.1% to 2% among different geographical regions and ethnic groups. In some cases this can be associated with other syndromes, such as autoimmune diseases. At present, it is generally accepted that the disease pathogenesis is multifactorial and genetically heterogeneous. Mutations or polymorphisms in several genes have now been associated with development of vitiligo. However, together they only account for a small proportion of the genetic susceptibility for vitiligo. Recent gene mapping studies have identified several major susceptibility loci for vitiligo, including evidence for a major vitiligo susceptibility locus on chromosome 4q12-q21 (AIS4) in Chinese population. However, the actual genes responsible have not been identified.Objective In order to investigate the possible genes associated with vitiligo in AIS4 loci, candidate gene strategy was adopted in this study to analyse the association of genetic variations among this loci with vitiligo.Methods KIT and PDGFRA gene were selected as candidate gene in this study. The entire coding sequence, exon-intron junctions, promoter regions and 5'-and 3'-untranslated regions of KIT and PDGFRA gene were sequenced among Chinese vitiligo patients and controls. Association analysis between vitiligo and common SNPs in KIT gene as well as PDGFRA gene was conducted in Chinese Han population based on sequencing results. Possible role of rare variations in vitiligo was also analysed and possible functional changes were investigated for some of the mutations.Results DNA samples from 143 Chinese vitiligo families and 480 sporadic patients as well as 480 controls were sequenced. No association between common SNPs in KIT gene and PDGFRA gene and vitiligo was identified. Five rare missense mutations in KIT, c.125G>C (p.G42A), c.205G>C (p.E69Q), c.251C>T (p.T84M), c.910A>G (p.T304A), and c.1312A>G (p.I438V), and four rare missense mutations, c.418G>T (V140L), c.2986G>A (E996K), c.3098A>T (D1033V), c.3154A>T (T1052S), plus a splice site mutation c.367-3 C>T, were identified in PDGFRA. These rare mutations were associated with vitiligo and some of them co-segregated with patients in vitiligo family and some were found in spratic cases. Further more, the mutation c.910A>G (p.T304A) in KIT gene was found to be loss-of-function mutation.Conclusions: We conclude that there are no SNPs within KIT gene and PDGFRA gene associated with vitiligo and some rare variations in these two genes may predispose to the development of vitiligo. To our knowledge, this is the first observation that mutations in a single gene in AIS4 can frequently predispose to vitiligo.