Haim-Munk syndrome and Papillon-Lefèvre syndrome are allelic mutations in cathepsin C
T C Harta b, P S Hartb, M D Michalecb, Y Zhanga, E Firatlic, T E Van Dyked, A Stabholze, A Zlorogorskif, L Shapirag, W A Soskolneg
a University
of Pittsburgh, School of Dental Medicine, Department of Oral
Medicine/Pathology, 628 Salk Hall, 3501 Terrace Street, Pittsburgh, PA
15261, USA, b University of Pittsburgh, School of Medicine,
Department of Human Genetics, Pittsburgh, PA 15261, USA, c Department of Periodontology, University of
Istanbul School of Dentistry, Istanbul, Turkey, d Boston
University, Goldman School of Dental Medicine, Department of
Periodontology and Oral Biology, Boston, MA 02118-2392, USA, e Department of Community Dentistry,
Hebrew University-Hadassah Faculty of Dental Medicine, Jerusalem,
Israel, f Department
of Dermatology, Hebrew University-Hadassah Medical Center, Jerusalem,
Israel, g Department of
Periodontology, Hebrew University-Hadassah Faculty of Dental Medicine,
Jerusalem, Israel
Correspondence to: Dr T C Hart, hart{at}cpc.pitt.edu
Revised version received 3 November 1999;
Accepted for publication 9 November 1999
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 (2126CT) in a Turkish family
with classical PLS. These findings provide evidence that PLS and HMS
are allelic variants of cathepsin C gene mutations.
Keywords: Papillon-Lefèvre syndrome; Haim-Munk syndrome; cathepsin C mutation; allelic mutations
© 2000 by J Med Genet
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