J Med Genet 2000;37:927-932
( December )
Identification of cathepsin C mutations in ethnically diverse
Papillon-Lefèvre syndrome patients
P S Harta, Y Zhangb, E Firatlic, C Uygurc, M Lotfazard, M D Michaleca, J J Marksb, X Lub, B J Coatesa, W K Seowe, R Marshalle, D Williamsf, J B Reedg, J T Wrighth, T C Harta b
a University of
Pittsburgh, Department of Human Genetics, Pittsburgh, PA 15261, USA, b University of Pittsburgh, School of Dental
Medicine, Department of Oral Pathology, Pittsburgh, PA 15261, USA, c University of Istanbul School of Dentistry,
Department of Periodontology, Istanbul, Turkey, d Shiraz
University of Medical Science, Department of Periodontics, Shiraz, Iran, e University of Queensland,
School of Dentistry, Department of Paediatric Dentistry, Brisbane,
Australia, f The Leicester Royal Infirmary, Leicester, UK, g Wilford Hall USAF Medical
Center, Department of Ophthalmology, Lockland AFB, TX, 78236, USA, h University
of North Carolina, Department of Pediatric Dentistry, Chapel Hill,
North Carolina, USA
Correspondence to: Dr T C Hart, Department of Oral Medicine/Pathology, University of
Pittsburgh, School of Dental Medicine, 614 Salk Hall, 3501 Terrace
Street, Pittsburgh, PA 15261, USA, hart{at}cpc.pitt.edu
Revised version received 8 September 2000;
Accepted for publication 9 September 2000
INTRODUCTION
Papillon-Lefèvre
syndrome (PLS) is an autosomal recessive disorder characterised by
palmoplantar keratoderma and severe, early onset periodontitis,
which results from deficiency of cathepsin C activity secondary to
mutations in the cathepsin C gene. To date, 13 different cathepsin C
mutations have been reported in PLS patients, all of which are
homozygous for a given mutation, reflecting consanguinity.
AIMTo evaluate the generality of
cathepsin C mutations in PLS, we studied an ethnically diverse group of
20 unrelated families.
METHODSMutations were identified
by direct automated sequencing of genomic DNA amplified for exonic
regions and associated splice site junctions of the cathepsin C gene.
Long range PCR was performed to determine the genomic structure of the
cathepsin C gene.
RESULTSThe cathepsin C gene spans
over 46 kb, with six introns ranging in size from 1.6 to 22.4 kb.
Eleven novel mutations and four previously reported mutations were
identified in affected subjects from 14 families. Missense mutations
were most common (9/15), followed by nonsense mutations (3/15),
insertions (2/15), and deletions (1/15). Among these 14 probands, two
were compound heterozygotes. Affected subjects with transgressions of
the dermal lesions onto the knees or elbows or both had mutations in
both the pro- and mature regions of the enzyme, although most were in
the mature region.
CONCLUSIONMutations in the mature
region of cathepsin C were more likely to be associated with the
transgressions of the dermatological lesions, although the results were
not statistically significant. A comprehensive list of all cathepsin C
mutations described to date, representing 25 mutations from 32 families
with PLS and related conditions, is also presented.
Keywords:
cathepsin C;
genetics;
severe early onset
periodontitis;
hyperkeratosis
© 2000 by J Med Genet
