KITLG – familial progressive hyper- and hypopigmentation

Familial progressive hyper- and hypopigmentation (FPHH) is an autosomal dominant pigmentary disorder characterized by progressive, diffuse hyperpigmented macules intermingled with scattered hypopigmented spots, lentigines and café-au-lait lesions. Heterozygous variants in KITLG have been established as the cause of FPHH (MONDO:0017239).

A genome-wide linkage analysis in seven families mapped FPHH to 12q21.12-q22, identifying three missense substitutions (p.Val33Ala, p.Thr34Pro, p.Asn36Ser) co-segregating in four families, with a maximum LOD score of 4.35 (four families) (PMID:21368769). Subsequent targeted sequencing in two Chinese FPHH probands revealed a recurrent c.101C>T (p.Thr34Ile) and a novel c.104A>T (p.Asn35Ile) within the conserved VTNNV motif, both predicted deleterious by in silico tools (PMID:33407466). A de novo c.329A>T (p.Asp110Val) variant in exon 4 was later identified in a singleton case, expanding the mutational spectrum beyond exon 2 (PMID:34716665).

Missense variants cluster within or adjacent to the VTNNV core (amino acids 33–37), with eight distinct alleles reported to date. No loss-of-function or splice variants have been associated with FPHH, consistent with a gain-of-function mechanism. The prototypical variant c.107A>G (p.Asn36Ser) exemplifies this spectrum and is used here as a representative allele.

Functional studies demonstrate that soluble KITLG^Asn36Ser increases melanin content by 109% over wild-type in A375 melanoma cells and enhances tyrosinase activity, confirming a gain-of-function effect on melanogenesis (PMID:19375057). These data concord with the hyperpigmented phenotype observed in patients.

No studies have contradicted the AD inheritance or mechanistic model; no variants have been reported in unaffected controls or linked to alternative phenotypes in FPHH cohorts.

Together, genetic linkage, segregation in multiple families, independent replication across populations and concordant functional assays establish a Definitive gene–disease association. KITLG gain-of-function variants in the VTNNV motif drive melanocyte hyperactivity with interspersed hypopigmentation, supporting molecular diagnosis and targeted genetic counseling.

Key Take-home: Heterozygous KITLG missense mutations clustering in the VTNNV motif cause autosomal dominant FPHH via gain-of-function, enabling precise genetic testing and risk assessment.

References

• The Journal of investigative dermatology • 2011 • KITLG mutations cause familial progressive hyper- and hypopigmentation PMID:21368769
• BMC medical genomics • 2021 • Identification of a novel mutation in the KITLG gene in a Chinese family with familial progressive hyper- and hypopigmentation PMID:33407466
• The Journal of dermatology • 2020 • Novel mutation in the KITLG gene in familial progressive hyperpigmentation with or without hypopigmentation. PMID:32189379
• Molecular genetics & genomic medicine • 2021 • De novo mutation in KITLG gene causes a variant of Familial Progressive Hyper- and Hypo-pigmentation (FPHH). PMID:34716665
• American journal of human genetics • 2009 • Gain-of-function mutation of KIT ligand on melanin synthesis causes familial progressive hyperpigmentation. PMID:19375057

Evidence Based Scoring (AI generated)