Submission Details

Autosomal recessive

04/10/2019

The CTSA gene is located on chromosome 20 at 20q13.12 and encodes the protein cathepsin A, which is also called lysosomal protective protein/cathepsin A, or PPCA. This protein is active in lysosomes and plays a critical role in supporting the stability andactivity of beta-galactosidase and neuraminidase. Cathepsin A can also act as a protease. CTSA was first reported in relation to autosomal recessive galactosialidosis in 1993 (8514852: Shimmoto et al. 1993). At least 27 unique variants have been reported in humans, including small deletions/insertions, missense mutations, splicing variants and only one nonsense mutation (28603679: Annunziata & d’Azzo 2017). Recurrent variants include a splice region variant resulting in skipping of exon 7 and two missense variants, Phe458Val and Tyr267Asn. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Seven cases with variants in this gene were evaluated to support this curation (8514852: Shimmoto et al. 1993; 24769197: Prada et al. 2014; 29876240: Okulu et al. 2017; 28555253: Kartal et al. 2017). Segregation data were not available. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. Genetic and experimental data indicate the mechanism for disease is homozygous loss of function. This gene-disease relationship is supported by biochemical function data, a knockout mouse model that recapitulates the human disease, and rescue of the biochemical, morphological, and histological features in homozygous null mice by transplantation of bone marrow from a transgenic line overexpressing WT human CTSA in erythroid precursor cells (7590240: Zhou et al. 1996; 28603679: Annunziata & d’Azzo 2017). In summary, CTSA is definitively associated with autosomal recessive galactosialidosis. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time.

8514852 24769197 29876240 28555253 28603679 7590240