CTSK – Pycnodysostosis

Pycnodysostosis is a rare autosomal recessive skeletal dysplasia characterized by disproportionate short stature, delayed closure of cranial sutures, generalized osteosclerosis, acro-osteolysis of the distal phalanges, and increased fracture risk. Biallelic loss-of-function variants in CTSK, encoding the osteoclast‐expressed cysteine protease cathepsin K, underlie the disease [PMID:8938428; PMID:9529353].

1. Clinical Validity

Inheritance is autosomal recessive. Segregation of homozygous or compound heterozygous CTSK variants in consanguineous families and a uniparental disomy case confirms recessive transmission [[PMID:8938428]]; [[PMID:9529353]]. Across 59 independent families comprising 159 patients, diverse CTSK variants segregate with pycnodysostosis, and Ctsk–/– mice recapitulate the phenotype, supporting a Strong gene–disease association [[PMID:21569238]].

2. Genetic Evidence

To date, over 33 distinct CTSK mutations have been described, including missense, nonsense, splice‐site, and frameshift changes distributed throughout prepro, prodomain, and mature regions. A recurrent founder allele c.830C>T (p.Ala277Val) has been reported in multiple populations [[PMID:19674475]]. Variants cluster in exons 5–7, with hotspot founder mutations identified in Brazilian and Saudi cohorts [[PMID:27558267]].

3. Functional Evidence

In vitro expression of key mutants demonstrates loss of cathepsin K activity: proregion misfolding (e.g., p.Gly79Glu) and mature‐domain instability abolish collagenase function [[PMID:10074491]]. Ctsk–/– murine models display osteosclerotic, low-resorption phenotypes analogous to human pycnodysostosis, confirming haploinsufficient loss-of-function mechanism [[PMID:21569238]].

4. Mechanism of Pathogenicity

Cathepsin K deficiency impairs type I collagen degradation in the osteoclast resorption lacuna, leading to bone matrix accumulation, osteoclast dysfunction, and skeletal fragility. Biomarker studies show reduced collagen telopeptide release and paradoxical accumulation of larger C-terminal fragments in patient samples [[PMID:10571690]].

5. Integration and Clinical Utility

Robust genetic and experimental data establish a Strong association between CTSK and pycnodysostosis. Molecular diagnosis via targeted sequencing is definitive and informs genetic counseling, carrier testing, and functional studies. Early recognition enables multidisciplinary care to mitigate fracture risk and manage craniofacial complications.

Key Take-home: Biallelic CTSK variants cause autosomal recessive pycnodysostosis through cathepsin K loss of function, with diagnostic confirmation by genetic testing guiding clinical management.

References

• Genome research • 1996 • A nonsense mutation in the cathepsin K gene observed in a family with pycnodysostosis. PMID:8938428
• American journal of human genetics • 1998 • Paternal uniparental disomy for chromosome 1 revealed by molecular analysis of a patient with pycnodysostosis. PMID:9529353
• Orphanet journal of rare diseases • 2011 • Clinical and animal research findings in pycnodysostosis and gene mutations of cathepsin K from 1996 to 2011. PMID:21569238
• The Journal of clinical investigation • 1999 • Characterization of novel cathepsin K mutations in the pro and mature polypeptide regions causing pycnodysostosis. PMID:10074491
• Journal of bone and mineral research • 1999 • Determination of bone markers in pycnodysostosis: effects of cathepsin K deficiency on bone matrix degradation. PMID:10571690
• The FEBS journal • 2018 • Not all pycnodysostosis-related mutants of human cathepsin K are inactive – crystal structure and biochemical studies of an active mutant I249T. PMID:30199612

Evidence Based Scoring (AI generated)