Genotype-phenotype Correlation In One Epidermolytic Palmoplantar Keratoderma And Two Pachyonychia Congenital Type ⅠPedigrees

Background:Epidermolytic palmoplantar keratoderma （EPPK） is a rare autosomal dominant genodermatoses, characterized by diffuse waxy thickening of palms and soles surrounded by an erythematous border with histologic findings of vacuolar degeneration in the granular layer. EPPK is generally associated with dominant-negative mutations of KRT9, while a small number of cases have been reported where pathogenic mutations were identified in KRT1. Meanwhile, EPPK caused by KRT9mutation is different from that caused by KRT1, which can be discriminated by clinical histopathological features and hyperkeratosis distribution. Mutations in the KRT6A or KRT16gene cause pachyonychia congenital type1（PC-1）, while mutations in KRT17or KRT6B underlie PC-2.Objectives:To identify the causative mutation in a Chinese EPPK and two PC-1pedigrees, and investigate the genotype-phenotype of EPPK/PC-1and the corresponding mutation.Methods:All3families collected were from Southeast China. To map the camptodactyly phenotype in an initial approach, microsatellite markers flanking KRT9, GJB6, and GJB2, and candidate loci for camptodactyly-like phenotypes on chromosomes3q11.2-q13.12,1q24-q25（PRG4）,4p16.3（FGFR3） and16q11.1-q22were selected and genotyped. Then the whole coding regions of KRT9in EPPK family and KRT6A/KRT16/KRT17/KRT6B in PC-1families were amplified and directly sequenced to detect the mutation. The variants were confirmed by RFLP and RT-PCR analysis.Results:In EPPK family, haplotype analysis excluded the known candidate loci for camptodactyly and/or knuckle pad-like phenotypes on chromosomes13q12,3qll.2-q13.12,1q24-q25,4p16.3and16q11.1-q22, while only the markers D17S1787and D17S579flanking KRT9showed co-segregation with EPPK. Then a novel C.T1373C （p.L458P） mutation within the sixth exon of KRT9was validated. Meanwhile, Two novel de novo mutations, a splice acceptor site variant IVS8-2A>C （p.S487FfsX72） in KRT6A and a heterozygous substitution c.AA373₃74GG （p.N125G） within exon1of KRT16were found separately in two PC-1families.（European Journal of Dermatology,2011;21（5）:675-679and accepted with revision）Conclusions:A similar phenotype may originate from mutations in different genes, and defects in various structural proteins may have phenotypically similar dominant-negative effects, thus we speculate that KRT9plays a complex role in the development of EPPK with knuckle pads and camptodactyly. Genotype-phenotype correlations among PC-1patients with codon-125mutation in KRT16were established, while the phenotypes caused by the IVS8-2A>C mutation in KRT6A needs further studies to confirm as a result of the rare feature:fissured tongue.