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Familial primary localized cutaneous amyloidosis (FPLCA) is an autosomal dominant disorder characterized by chronic pruritus and deposition of keratin filament–associated amyloid in the dermis. Through linkage to 5p13.1–q11.2 and candidate gene analysis, heterozygous missense mutations in OSMR were identified in multiple families with FPLCA (PMID:18179886; PMID:20507362).
In the initial report, three unrelated families harbored the extracellular-domain variants c.1853G>C (p.Gly618Ala) and c.2072T>C (p.Ile691Thr) in OSMRbeta, co-segregating with disease and mapping to fibronectin type III–like domains critical for receptor dimerization (PMID:18179886). A subsequent study in two Dutch pedigrees described additional heterozygous missense alleles p.Val631Leu and p.Asp647Tyr with concordant segregation in affected individuals (PMID:20507362).
Across five independent families, four distinct missense variants in OSMR associate with FPLCA under an autosomal dominant inheritance pattern, with consistent co-segregation of pathogenic alleles. The variant spectrum is entirely missense, clustering in extracellular domains that mediate ligand binding and receptor dimerization.
Functional assays in patient‐derived keratinocytes demonstrate markedly reduced activation of JAK/STAT, MAPK, and PI3K/Akt pathways upon stimulation with oncostatin M or interleukin-31, indicating impaired OSMR signaling as a disease mechanism (PMID:18179886). These findings support a dominant-negative or haploinsufficient mechanism leading to amyloid deposition and chronic itching.
No conflicting evidence for OSMR involvement in FPLCA has been reported. Overall, the genetic and experimental data provide a robust association between OSMR mutations and FPLCA.
Key Take-home: OSMR screening in patients with autosomal dominant cutaneous amyloidosis informs diagnosis and enables molecular confirmation in FPLCA.
Gene–Disease AssociationStrongMissense variants identified in five unrelated families with co-segregation and consistent phenotype Genetic EvidenceStrongFour distinct missense OSMR variants in five probands across five families ([PMID:18179886], [PMID:20507362]) Functional EvidenceModeratePatient keratinocytes exhibit deficient JAK/STAT, MAPK, and PI3K/Akt signaling upon OSM/IL-31 stimulation ([PMID:18179886]) |