Loss-of-function mutations in the cathepsin C gene result in periodontal disease and palmoplantar keratosis

Abstract

Papillon-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 patients. 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 onset. 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.

MEPE has the properties of an osteoblastic phosphatonin and minhibin

“…Mineral maturity (mineral crystal size and perfection) throughout all anatomic regions of the osteopontin knock-out mouse bone is also significantly increased [10]. Of additional interest is the recent finding that loss of function mutations in the cathepsin C gene is the primary cause of Papillon-Lefevre syndrome (PLS) [88]. PLS results in periodontopathia with loss of both deciduous and permanent dentitions and severe intracranial calcifications [88].…”

“…Of additional interest is the recent finding that loss of function mutations in the cathepsin C gene is the primary cause of Papillon-Lefevre syndrome (PLS) [88]. PLS results in periodontopathia with loss of both deciduous and permanent dentitions and severe intracranial calcifications [88]. MEPE is abundantly expressed in both brain (man/primates) and odontoblasts/osteoblasts (rodents and man/primates) [26,45,71].…”

“…Thus, we conclude that MEPE is a good OB-PTN candidate and the MEPE ASARM peptide inhibitory effects on mineralization are likely modulated by a novel PHEX-MEPE interaction. Of major interest in this regard is the recent finding that MEPE (OF45) knock-out mice have accelerated mineralization and increased bone formation [26] and loss of function mutations in the cathepsin C gene are responsible for the dental disease and ectopic intracranial calcification in PLS [88].…”

Revised nomenclature and classification of inherited ichthyoses: Results of the First Ichthyosis Consensus Conference in Sorèze 2009

“…3,124 Diseases related to inherited ichthyoses A certain number of MEDOC forms can be regarded as phenotypically and/or etiologically related to ichthyosis, or have to be considered as differential diagnoses. Examples are the PPKs, which sometimes show nonacral involvement, eg, Vohwinkel keratoderma 127 caused by a particular dominant GJB2 mutation (connexin 26), 128 Mal de Meleda 129 caused by recessive SLURP1 mutations, 130 and Papillon-Lefèvre syndrome 131 caused by recessive CTSC mutations encoding cathepsin C. 132 Mutations in keratin 5 or 14 cause epidermolysis bullosa simplex, 133,134 which can present with severe neonatal blistering clinically indistinguishable from EI. 62,65,135 Importantly, hypohidrosisea common symptom in ichthyoses, especially ARCI 136 erepresents one main criterion for the heterogeneous group of the ectodermal dysplasia.…”

Death penalty for keratinocytes: apoptosis versus cornification

“…76 Genetic mapping revealed that the mutations in the autosomal recessive Papillon-Lefevre syndrome, marked by premature tooth loss and palmoplantar keratosis, result in loss-of-function of the cathepsin C gene. 77 Furthermore, cathepsin L2 has been detected in stratum corneum extracts. 78 This protease seems to be activated during epidermal differentiation and secreted into the intercellular space.…”