KITLG Mutations Cause Familial Progressive Hyper- and Hypopigmentation

Abstract

Familial progressive hyper- and hypopigmentation (FPHH) is thought to be an autosomal dominant disorder with reduced penetrance. Clinical signs consist of progressive diffuse, partly blotchy hyperpigmented lesions, multiple café-au-lait spots, intermingled with scattered hypopigmented-appearing maculae, and lentigines. FPHH is distinct from familial progressive hyperpigmentation (FPH), in which no hypopigmented features are present, and which is phenotypically and histologically closer to Dyschromatosis Universalis Hereditaria 2 (DUH2). It also differs from the Legius syndrome, characterized by familial café-au-lait spots and skin fold freckling, caused by mutations in SPRED1. We performed a genome-wide linkage analysis in seven families with FPHH, and identified linkage on 12q21.12-q22, which overlaps with the DUH2 locus. We investigated whether KITLG in the locus is mutated in FPHH. We discovered three different mutations in four families. A reported FPH substitution was observed in two FPHH families, and two, to our knowledge, previously unreported substitutions, p.Val33Ala and p.Thr34Pro, cosegregated with FPHH in two separate families. All three mutations were located in a conserved β-strand in KITLG, suggesting its important role in the activation of the KITLG receptor c-Kit. In aggregate, mutations in a single gene cause various pigmentation disorders: FPH, FPHH, and likely DUH2. Therefore, KITLG is an important modulator of skin pigmentation.

Colorful DNA polymorphisms in humans

“…KITLG (12q22) encodes the c-Kit ligand that influences melanocyte proliferation and activates keratinocytes to produce promelanogenic factors [151]. KITLG mutations have been found to cause familial progressive hyperand hypopigmentation [152,153]. Variants at the KITLG locus have been associated with light hair colors in Europeans [17,147,154].…”

Molecular screening strategies for NF1-like syndromes with café-au-lait macules

“…Clinical signs are somewhat different from its allelic disorder FPH (59), in which no hypopigmentation is present. Notably, the mutation p.Asn36Ser results in FPH and FPHH, with the FPH patient image in a previous study by Wang et al (59) also demonstrating small suspicious hypopigmented lesions (54). This suggests these two disorders may resemble another pigmentary genetic disorder termed Dowling-Degos disease (DDD; OMIM 179850, 615327 and 615696) (60–63), which may also be the same condition with a degree of phenotypic variability, for example, in the distribution of hyperpigmented and hypopigmented lesions.…”

“…Of the three reported piebaldism cases with multiple CALM and intertriginous freckling, all the mutations were located in the tyrosine kinase (TK) domain (Gly610Asp, Gliu640Asp and Arg791Gly) (51–53). It has been demonstrated that inadequate phosphorylation of the KIT-binding domain in SPRED1 due to a defective KIT TK would result in loss of inhibition of the Ras⁄MAPK signaling pathway, leading to a phenotype similar to NFLS (53), while gain-of function mutations in KITLG have been reported to result in FPHH (54), indicating KIT and KITLG are important modulators of skin pigmentation.…”

“…2) (6). It is the result of a mutation in KITLG , encoding KITLG involved in the Ras⁄MAPK signaling pathway (54). Clinical signs are somewhat different from its allelic disorder FPH (59), in which no hypopigmentation is present.…”

Familial progressive hyper- and hypopigmentation: a report on a Chinese family and evidence for genetic heterogeneity

“…3 A genome-wide linkage analysis of seven families with FPHH was performed, and it identified a linkage on 12q21.12-q22 in a recent report. 4 Then, the mutations of a single gene, KITLG, were discovered to cause various pigmentation disorders: FPH, FPHH, and likely dyschromatosis universalis hereditaria 2 (DUH2). The gain-of-function mutation of the KITLG gene affects melanin synthesis and causes familial progressive hyperpigmentation, and importantly, KITLG is expressed locally in the epidermal keratinocytes and endothelial cells of human skin.…”