A nonsense mutation in the cathepsin K gene observed in a family with pycnodysostosis.

Abstract

Pycnodysostosis (MIM 265800) is a rare, autosomal recessive skeletal dysplasia characterized by short stature, wide cranial sutures, and increased bone density and fragility. Linkage analysis localized the disease gene to human chromosome 1q21, and subsequently the genetic interval was narrowed to between markers D1S2612 and D1S2345. Expressed sequence tagged markers corresponding to cathepsin K, a cysteine protease highly expressed in osteoclasts and thought to be important in bone resorption, were mapped previously in the candidate region. We have identified a cytosine to thymidine transition at nucleotide 862 (GenBank accession no. S79895) of the cathepsin K coding sequence in the DNA of an affected individual from a large, consanguinous Mexican family. This mutation results in an arginine to STOP alteration at amino acid 241, predicting premature termination of cathepsin K mRNA translation. All affected individuals in this family were homozygous for the mutation, suggesting that this alteration may lead to pycnodysostosis. Recognition of the role of cathepsin K in the etiology of pycnodysostosis should provide insights into the pathogenesis and treatment of other disorders of bone remodeling, including osteoporosis.

Cathepsin K gene mutations and 1q21 haplotypes in patients with pycnodysostosis in an outbred population

“…The second explanation would suggest the non-core haplotype chromosome in II:2 is much more distantly related than the other seven core-haplotype chromosomes. Our results confirm the disease locus previously reported [6][7][8][9][10][11] and show that at least three mutations exist in the Danish population. Consequently, this study indicates locus homogeneity and allele heterogeneity in pycnodysostosis within an outbred population.…”

“…U13665), a cystein protease gene highly expressed in osteoclasts, have been found to be responsible for pycnodysostosis. Three intragenic mutations were reported 6,7 in three large inbred families with Moroccan Arab, American Hispanic and Israeli Arab ethnic backgrounds, respectively. Three mutations were found in two non-consanguineous families of different ethnic origin.…”

Molecular Understanding of Osteoclast Differentiation and Physiology

“…Cathepsin K knockout mice develop osteopetrosis due to a deficit matrix degradation but not demineralization [26]. Similarly, mutations in the human cathepsin K gene have demonstrated an association with a rare skeletal dysplasia, pycnodysostosis [27,28]. Tartrate-resistant acid phosphatase (TRAP, encoded by Acp5), an osteoclast differentiation marker, as well as cathepsin K also affect the functional activity of osteoclast by regulating bone matrix resorption and collagen turnover [29].…”

An atypical subtrochanteric femoral fracture from pycnodysostosis: A lesson from nature

“…(2) Genetic linkage analysis of two kindreds assigned the locus for pycnodysostosis to chromosome 1q21, and missense, nonsense, and stop mutations involving the cathepsin K gene were found subsequently to cosegregate with the disease. (3)(4)(5) Cathepsin K is a lysosomal cysteine protease highly expressed in osteoclasts alone, thereby restricting the phenotype of pycnodysostosis to bone. (6) The treatment of pycnodysostosis is restricted to symptomatic management of fractures and other skeletal problems, but insights provided by identification of underlying gene mutations have led to the development of cathepsin K inhibitors for the treatment of osteoporosis.…”