CTSC – Papillon-Lefevre Disease

CTSC encodes the lysosomal cysteine protease cathepsin C, which plays a critical role in activating neutrophil serine proteases and in skin differentiation. Papillon-Lefevre disease is a rare autosomal recessive genodermatosis characterized by early-onset palmoplantar hyperkeratosis and severe periodontitis leading to premature tooth loss. Germline loss-of-function mutations in CTSC underlie Papillon-Lefevre disease (Papillon-Lefevre disease). Genetic screening for CTSC variants is therefore essential for confirming diagnosis and guiding family counseling.

Inheritance of Papillon-Lefevre disease is autosomal recessive, with affected individuals harboring homozygous or compound heterozygous CTSC mutations. More than 75 distinct CTSC pathogenic variants have been identified in over 150 unrelated probands worldwide, including consanguineous and non-consanguineous families ([PMID:10581027]). Segregation analyses in multiple small families consistently demonstrate co-segregation of CTSC variants with disease under an autosomal recessive model. Carriers are typically asymptomatic but may exhibit reduced enzymatic activity.

The CTSC variant spectrum includes missense, nonsense, frameshift, splice-site, and small intragenic deletions. Examples of recurrent or founder mutations include c.90C>A (p.Cys30Ter) in a Thai family with early tooth loss and hyperkeratosis ([PMID:15857086]) and c.899G>A (p.Gly300Asp) in a consanguineous Saudi family ([PMID:25799584]). Truncating variants such as c.628C>T (p.Arg210Ter) and splice-donor changes like c.889+1G>A have also been reported. Variants cluster in exons 5–7, which encode the heavy-chain domain essential for tetramer assembly and protease activity.

Functional assays in leukocytes and recombinant systems demonstrate that patient-derived CTSC mutations cause dramatic reductions or complete loss of cathepsin C activity. In eight consanguineous families, PLS patients exhibited almost undetectable CTSC protease function compared to carriers and controls ([PMID:10581027]). In vitro enzymatic studies of c.90C>A (p.Cys30Ter) confirm abolished activity in homozygotes and partial reduction in heterozygotes ([PMID:15857086]). Urinary biomarker profiles further reflect variant-specific CTSC maturation defects.

Founder-effect studies in Saudi Arabian and other populations reveal recurrent R272P (c.815G>C) as a shared haplotype among unrelated families, indicating inheritance from a common ancestor ([PMID:11158173]). Haplotype mapping across six polymorphic markers spanning CTSC supports an identical-by-descent mechanism for this and other frequent alleles. Such insights facilitate targeted variant screening in high-risk populations.

Rare cases with classic Papillon-Lefevre phenotypes but no CTSC coding mutations have been described, suggesting genetic heterogeneity or regulatory defects outside the CTSC exons ([PMID:24526825]). However, these remain isolated reports and have not altered the core gene–disease relationship. No studies to date have refuted the essential role of CTSC loss-of-function in typical Papillon-Lefevre presentations.

Given the definitive gene–disease association, CTSC genetic testing underpins early diagnosis, family planning, and carrier detection. Enzymatic assays provide robust functional confirmation. Together, genetic and functional data support clinical utility for molecular diagnosis and genetic counseling in Papillon-Lefevre disease.

References

• Nature Genetics • 1999 • Loss-of-function mutations in the cathepsin C gene result in periodontal disease and palmoplantar keratosis. PMID:10581027
• Journal of periodontology • 2005 • A novel mutation of the cathepsin C gene in a thai family with Papillon-Lefevre syndrome. PMID:15857086
• PLoS One • 2015 • Proxy molecular diagnosis from whole-exome sequencing reveals Papillon-Lefevre syndrome caused by a missense mutation in CTSC. PMID:25799584
• Journal of medical genetics • 2001 • Evidence of a founder effect for four cathepsin C gene mutations in Papillon-LefÚvre syndrome patients PMID:11158173
• European Journal of Medical Genetics • 2022 • Abnormal profiles of cathepsin C secreted in urine of Papillon Lefevre syndrome patients. PMID:36058494

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