Mutation Analysis Of The Genes In Familial Primary Localized Cutaneous Amyloidosis And Pachyonychia Congenita

Background: Both familial primary localized cutaneous amyloidosis(FPCA)and pachyonychia congenita(PC) are rarely autosomal-dominant genodermatosis.FPCA is characterized by papule occurring typically over the shins with chronic skin itching and deposition of epidermal keratin filament-associated amyloid material in the dermis. FPCA has been mapped early to chromosome 5 and 11 pathogenic missense mutations in the OSMR gene, which encodes the interleukin-6 family cytokine receptor oncostatin M-specific receptor beta(OSMRβ), were reported. The precise pathogenesis of FPCA is unclear and a effective and treatment of FPCA is absent in clinic. Also PC Ⅱtype is a rare disease which is associated with palmoplantar hyperkeratosis, natal tooth and steatocystoma multiplex. So far, K17 gene and K6 b gene have been reported as part of the pathogenesis of PC. There is no effective therapy for pachyonychia congenita.Objective: To identify mutation in the OSMR gene in a pedigree with FPCA and the the K17 and K6 b gene in a pedigree with PC Ⅱtype.Methods: We collected a pedigree with FPCA and a pedigree with PC. We executed congo red staining in lesional skin biopsy of the proband of FPCA.Genomic DNA was respectively extracted from peripheral blood samples obtained from the two pedigrees, and subjected to PCR for the amplification of encoding exons and their flanking sequences of the relevant gene followed by Sanger sequencing. The sequencing results were analyzed with BioEdit Sequence Alignment Editor. We performed gene mutation detection of the other members of the family and 50 normal subjects to rule out mutations polymorphism after preliminary founding the locus.Results: 1.A pedigree including 7 individuals affected with FPCA was enrolled in this study. The pedigree consists of 47 members. Histopathology of lesional skin showed orange crumb material in the superficial papillary dermis by congo red staining. A heterozygous missense mutation c.2081C>T, which leads to the substitution of proline by threonine at position 694, was detected in the OSMR geneof the proband. All the affected individuals harbored this mutation, while the normal individuals did not have this mutation. This mutation was co-segregated with FPCA phenotype in the family and was not detected in 50 normal subjects.2. A pedigree affected with PC was enrolled in this study. A heterozygous missense mutation c.275A>G, which leads to the substitution of Asparagine by Serine at position 92, was detected in the K17 gene. The father who has the same phenotype harbored this mutation, while the normal individuals and the healthy controls did not have this mutation. There was no mutation in K6 b gene.Conclusion: 1.The heterozygous mutation p.P694 T of OSMR gene may be the cause of clinical phenotypes of FPCA in this family.2.The heterozygous mutation p.N92 S of K17 gene may be the cause of clinical phenotypes of PC in this family.3.For some monogenic hereditary skin diseases, genetic diagnosis may become a feasible method to diagnose atypical cases.