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Haim-Munk syndrome and Papillon-Lefèvre syndrome are allelic mutations in cathepsin C
T C Hart1, P S Hart, M D Michalec
1University of Pittsburgh, School of Dental Medicine, Department of Oral Medicine/Pathology, 628 Salk Hall, 3501 Terrace Street, Pittsburgh, PA 15261, USA. hart@cpc.pitt.edu
Insights
Papillon-Lefèvre syndrome (PLS) and Haim-Munk syndrome (HMS) are linked to palmoplantar keratoderma and severe periodontitis. Genetic analysis reveals cathepsin C gene mutations are responsible for both PLS and HMS, indicating they are allelic variants.
Area of Science:
- Genetics
- Dermatology
- Periodontology
Background:
- Palmoplantar keratoderma (PPK) encompasses various conditions, with Papillon-Lefèvre syndrome (PLS) and Haim-Munk syndrome (HMS) uniquely presenting with premature destructive periodontitis.
- While both PLS and HMS share PPK and severe periodontitis, HMS is distinguished by additional findings like arachnodactyly and acro-osteolysis.
- HMS cases are primarily documented in a specific Indian isolate from Cochin, unlike PLS, which is globally distributed. Parental consanguinity is noted in both conditions.
Purpose of the Study:
- To investigate the genetic basis of Haim-Munk syndrome (HMS) by examining the cathepsin C gene.
- To determine if mutations in the cathepsin C gene are responsible for both Haim-Munk syndrome (HMS) and Papillon-Lefèvre syndrome (PLS).
Main Methods:
- Sequencing of the cathepsin C gene in affected and unaffected individuals from the Cochin isolate.
- Analysis of genetic loci flanking the cathepsin C gene to assess inheritance patterns.
- Comparison of cathepsin C gene mutations in HMS patients with those in a Turkish family presenting with classical PLS.
Main Results:
- A specific mutation in cathepsin C (exon 6, 2127A--> G), altering a conserved amino acid, was identified and segregated with HMS in four nuclear families.
- A shared common haplotype surrounding the cathepsin C gene in affected individuals from the Cochin isolate suggests a common ancestor and autosomal recessive inheritance for HMS.
- A distinct mutation in the same exon of the CTSC gene (codon 2126C-->T) was found in a Turkish family with PLS.
Conclusions:
- Cathepsin C gene mutations are the underlying cause of Haim-Munk syndrome (HMS) in the studied population.
- Papillon-Lefèvre syndrome (PLS) and Haim-Munk syndrome (HMS) are allelic variants resulting from different mutations in the cathepsin C gene.
- These findings clarify the genetic relationship between PLS and HMS, attributing both to defects in the cathepsin C gene.
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, acro-osteolysis, 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 affected and unaffected 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 affected 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.
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