Nature Genetics
23, 421 - 424 (1999)
doi:10.1038/70525
Loss-of-function mutations in the cathepsin C gene result in periodontal
disease and palmoplantar keratosisCarmel Toomes1, 2, 12, Jacqueline James3, 12, A. Joseph Wood1, 12, Chu Lee Wu1, 12, Derek McCormick4, Nicholas Lench5, Chelsee Hewitt1, Leanne Moynihan5, Emma Roberts5, C. Geoffrey Woods6, Alexander Markham5, Melanie Wong7, Richard Widmer8, Khaled Abdul Ghaffar9, Michael Pemberton3, Ibtessam Ramzy Hussein10, Samia A. Temtamy10, Robin Davies11, Andrew P. Read1, Philip Sloan3, Michael J. Dixon2, 3
& Nalin S. Thakker1, 31
Department of Medical Genetics, St. Mary's Hospital
, Manchester, UK. 2
School of Biological Sciences, University of Manchester,
Stopford Building, University of Manchester, Manchester,
UK. 3
Department of Dental Medicine and Surgery, Turner Dental
School, University of Manchester, Manchester, UK.
4
Department of Oncology, Queens University of Belfast,
Belfast City Hospital Tower, Belfast, UK. 5
Molecular Medicine Unit, St. James's University Hospital
, Leeds, UK. 6
Department of Clinical Genetics, St. James's University
Hospital, Leeds, UK. 7
Department of Immunology and Infectious Diseases, New
Children's Hospital, Westmead, New South Wales, Australia
. 8
Department of Paediatric Dentistry, Westmead Hospital
Dental Clinical School, Westmead, New South Wales,
Australia. 9
Department of Oral Diagnosis and Periodontology, Eins-Shams
University, Cairo, Egypt. 10
Department of Human Genetics, National Research Centre
, Cairo, Egypt. 11
Dental Health Unit, Skelton House, Manchester
, UK. 12
The authors contributed equally to this work
Correspondence should be addressed to Nalin S. Thakker nthakker@man.ac.ukPapillon-Lefèvre syndrome, or keratosis palmoplantaris with periodontopathia
(PLS, MIM 245000), is an autosomal recessive disorder that is mainly ascertained
by dentists because of the severe periodontitis that afflicts patients1,
2. Both the deciduous and permanent dentitions are affected, resulting
in premature tooth loss. Palmoplantar keratosis, varying from mild psoriasiform
scaly skin to overt hyperkeratosis, typically develops within the first three
years of life. Keratosis also affects other sites such as elbows and knees.
Most PLS patients display both periodontitis and hyperkeratosis. Some patients
have only palmoplantar keratosis or periodontitis, and in rare individuals
the periodontitis is mild and of late onset3,
4,
5,
6. The PLS
locus has been mapped to chromosome 11q14−q21 (refs 7, 8, 9). Using homozygosity mapping in eight small consanguineous families,
we have narrowed the candidate region to a 1.2-cM interval between D11S4082 and D11S931. The gene (CTSC) encoding the lysosomal protease
cathepsin C (or dipeptidyl aminopeptidase I) lies within this interval. We
defined the genomic structure of CTSC and found mutations in all eight
families. In two of these families we used a functional assay to demonstrate
an almost total loss of cathepsin C activity in PLS patients and reduced activity
in obligate carriers.
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