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

Abstract

Of the many palmoplantar keratoderma (PPK) conditions, only Papillon-Lefèvre syndrome (PLS) and Haim-Munk syndrome (HMS) are associated with premature periodontal destruction. Although both PLS and HMS share the cardinal features of PPK and severe periodontitis, a number of additional findings are reported in HMS including arachnodactyly, acroosteolysis, atrophic changes of the nails, and a radiographic deformity of the fingers. While PLS cases have 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. Although autosomal recessive transmission of PLS is evident, a more "complex" autosomal recessive pattern of inheritance with phenotypic influences from a closely linked modifying locus has been hypothesised for HMS. Recently, mutations of the cathepsin C gene have been identified as the underlying genetic defect in PLS. To determine if a cathepsin C mutation is also responsible for HMS, we sequenced the gene in aVected and unaVected subjects from the Cochin isolate in which both the PLS and HMS phenotypes appear. Here we report identification of a mutation of cathepsin C (exon 6, 2127A→ G) that changes a highly conserved amino acid in the cathepsin C peptide. This mutation segregates with HMS in four nuclear families. Additionally, the existence of a shared common haplotype for genetic loci flanking the cathepsin C gene suggests that aVected subjects descended from the Cochin isolate are homozygous for a mutation inherited "identical by descent" from a common ancestor. This finding supports simple autosomal 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. (J Med Genet 2000;37:88-94)

Pyogenic Liver Abscess and Papillon-Lefèvre Syndrome: Not a Rare Association

“…35 Another related syndrome, Haim-Munk syndrome, was also found to have a mutation in the same gene and is now considered to be an allelic variant of PLS. 36 …”

Current and prospective applications of non-proteinogenic amino acids in profiling of proteases substrate specificity

“…Importantly, defi ciency of DPP-IV leads to Haim-Munk syndrome or Papillon-Lefevre syndrome (Hart et al , 2000 ). Li et al (2009) synthesized dipeptide derivatives attached to a rhodamine fl uorophore and monitored cathepsin C proteolytic activity in live cells by fl ow cytometry assay (FACS).…”

Cathepsin C is a tissue-specific regulator of squamous carcinogenesis

“…Principally an amino dipeptidase, CtsC cleaves two-residue units in the N terminus of polypeptide chains in a nonspecific manner (Turk et al 1998) and, unlike other cysteine Cts, exists in a tetrameric structure ) that blocks autoactivation . Although individuals with loss-of-function mutations in CtsC manifest prepubertal aggressive periodontitis (Noack et al 2004), Haim-Monk syndrome (Hart et al 2000), or Papillon-Lefevre syndrome (Frezzini et al 2004;Pham et al 2004), CtsC is also of interest due to its catalytic activation of several leukocyte-derived serine proteases, including granzymes A, B, and C; neutrophil elastase (NE); CtsG; proteinase 3; and mast cell chymase (Pham and Ley 1999;Wolters et al 2001;Adkison et al 2002;Mallen-St Clair et al 2004). CtsC expression by mast cells and neutrophils reduces survival during septic peritonitis (Mallen-St Clair et al 2004) and limits protection from experimental arthritis (Adkison et al 2002), respectively, indicating its role as a mediator of inflammation.…”