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KITLG mutations cause familial progressive hyper- and hypopigmentation
Mustapha Amyere1, Thomas Vogt, Joe Hoo
1Laboratory of Human Molecular Genetics, de Duve Institute, Université Catholique de Louvain, Brussels, Belgium.
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.
Insights
Genetic mutations in KITLG cause various skin pigmentation disorders, including familial progressive hyper- and hypopigmentation (FPHH). This study identified new KITLG mutations linked to FPHH, highlighting its role in skin pigmentation regulation.
Area of Science:
- Genetics
- Dermatology
- Molecular Biology
Background:
- Familial progressive hyper- and hypopigmentation (FPHH) is an autosomal dominant disorder characterized by distinct hyperpigmented and hypopigmented macules.
- FPHH is phenotypically distinct from familial progressive hyperpigmentation (FPH) and Legius syndrome, suggesting different genetic underpinnings.
Purpose of the Study:
- To identify the genetic cause of FPHH.
- To investigate the role of KITLG in FPHH pathogenesis.
Main Methods:
- Genome-wide linkage analysis was performed in seven FPHH families.
- Mutation screening of the KITLG gene was conducted in affected individuals.
Main Results:
- Linkage analysis identified a locus on chromosome 12q21.12-q22, overlapping with the DUH2 locus.
- Three distinct KITLG mutations were discovered in four FPHH families, including two novel substitutions (p.Val33Ala and p.Thr34Pro).
- These mutations were located in a conserved region of KITLG, suggesting functional importance.
Conclusions:
- Mutations in KITLG are responsible for FPHH and likely contribute to other pigmentation disorders like FPH and DUH2.
- KITLG is a critical regulator of skin pigmentation.
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