KITLG – Familial Progressive Hyperpigmentation

KIT ligand (KITLG) variants cause familial progressive hyperpigmentation (FPH), an autosomal-dominant skin disorder characterized by early-onset hyperpigmented patches that enlarge and multiply over time. Linkage mapping in a six-generation Chinese pedigree yielded a maximum LOD score of 4.35 (PMID:19375057). Sequencing identified a heterozygous NM_000899.5:c.107A>G (p.Asn36Ser) variant that fully cosegregated with FPH and was absent in unaffected relatives (PMID:19375057). In human A375 melanoma cells, the mutant sKITLG p.Asn36Ser increased melanin content by 109% and elevated tyrosinase activity compared to wild-type, confirming a gain-of-function mechanism (PMID:19375057).

To date, this variant represents the sole reported KITLG mutation associated specifically with MONDO:0007771, supporting a Limited level of clinical validity due to evidence from a single multigenerational family. While robust functional data corroborate the pathogenic effect, further unrelated case reports and segregation analyses are needed to upgrade the association. Key Take-home: KITLG p.Asn36Ser should be considered in diagnostic evaluations of familial progressive hyperpigmentation due to its established gain-of-function pathogenicity.

References

• American journal of human genetics • 2009 • Gain-of-function mutation of KIT ligand on melanin synthesis causes familial progressive hyperpigmentation PMID:19375057

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