Haim-Munk syndrome and Papillon-Lefevre syndrome are allelic mutations in cathepsin C

Of the many palmoplantar keratoderma (PPK) conditions, only Papillon-Lefevr e syndrome (PLS) and Haim-Munk syndrome (HMS) are associated with premature periodontal destruction. Although both PLS and HMS share the cardinal feat ures of PPK and severe periodontitis, a number of additional findings are r eported in HMS including arachnodactyly, acroosteolysis, atrophic changes o f the nails, and a radiographic deformity of the fingers. While PLS cases h ave been identified throughout the world, HMS has only been described among descendants of a religious isolate originally from Cochin, India. Parental consanguinity is a characteristic of many cases of both conditions. Althou gh antosomal recessive transmission of PLS is evident, a more "complex" aut osomal recessive pattern of inheritance with phenotypic influences from a c losely linked modifying locus has been hypothesised for HRIS. Recently, mut ations of the cathepsin C gene have been identified as the underlying genet ic defect in PLS. Tee determine ifa cathepsin C mutation is also responsibl e for HMS, we sequenced the gene in affected and unaffected subjects from t he Cochin isolate in which both the PLS and HMS phenotypes appear. Here we report identification of a mutation of cathepsin C (exon 6, 2127A--> Gr) th at changes a highly conserved amino acid in the cathepsin C peptide. This m utation segregates with HMS in four nuclear families. Additionally, the exi stence of a shared C for genetic loci flanking the cathepsin C gene suggest s that affected subjects descended from the Cochin isolate are homozygous f or a mutation inherited "'identical by descent'" from a common ancestor. Th is finding supports simple aurosomal recessive inheritance for HMS in these families. We also report a mutation of the same exon 6 CTSC codon (2126C-- >T) in a Turkish family with classical PLS. These findings provide evidence that PLS and HMS are allelic variants of cathepsin C gene mutations.