Submission Details

CTSK was first reported in relation to pycnodysostosis, an autosomal recessive lysosomal storage disorder, in 1996 (Gelb BD, et al., 1996, PMID: 8703060). CTSK encodes cathepsin K, a member of the papain family of cysteine proteinases, which plays an important role in osteoclast function. A deficiency of cathepsin K results in an increase of demineralized bone surrounding individual osteoclasts as they do not adequately degrade the organic matrix. Accumulation of bone matrix around the osteoclasts causes various symptoms including short stature, characteristic facial appearance (convex nasal ridge and small jaw with obtuse mandibular angle), osteosclerosis with increased bone fragility, acro-osteolysis of the distal phalanges, delayed closure of the cranial sutures, and dysplasia of the clavicle. The diagnosis of pycnodysostosis is established by characteristic clinical and radiographic features and/or biallelic pathogenic variants in CTSK identified by molecular genetic testing (Leblanc S, et al., 2020, PMID: 33151655).

Ten variants (5 missense, 1 splice site, 4 nonsense) that have been reported in nine probands in six publications (Gelb BD, et al., 1996, PMID: 8703060; Hou WS, et al., 1999, PMID: 10074491; Haagerup A, et al., 2000, PMID: 10878663; Markova TV, et al., 2022, PMID: 35315254; Arman A, et al., 2014, PMID: 24767306; Johnson MR, et al., 1996, PMID: 8938428), as well as one family with segregation information (Johnson MR, et al., 1996, PMID: 8938428), are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is loss of function.

This gene-disease relationship is also supported by experimental evidence including biochemical function of cathepsin K, animal models systems, and expression data. Individuals with pycnodysostosis show decreased degradation of the bone matrix proteins, leading to increased bone density due to the absence of cathepsin K (Bossard MJ, et al., 1996, PMID: 8647860). Knockout mouse models recapitulate most of the ultrastructural, histological, and radiological abnormalities observed in humans with pycnodystosis including osteopetrosis, enhanced bone fragility, predisposition to bone fractures, reduced size of long bones (leading to short stature), bone marrow hypoplasia, splenomegaly (although rare in humans), and craniofacial anomalies (Saftig P, et al., 1998, PMID: 9811821; Gowen M, et al., 1999, PMID: 10491212). The cathepsin K mRNA and protein appeared to be compartmentalized toward the membrane as visualized by the localization of the in-situ hybridization signal and immunoreactivity in osteoclastic cells (Littlewood-Evans A, et al., 1997, PMID: 9028530).

In summary, CTSK is definitively associated with pycnodysostosis. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.