CTSA

CTSA encodes protective protein/cathepsin A (PPCA), a lysosomal protein required for the functional stability of the lysosomal enzymes β-galactosidase (GLB1) and neuraminidase 1 (NEU1); loss of CTSA function causes secondary deficiency of both enzymes and underlies the lysosomal storage disorder galactosialidosis (PMID:23915561). This protective role has been confirmed directly in patient cells, where compound heterozygous CTSA mutations impair both β-galactosidase and neuraminidase activity (PMID:31044084). PPCA activity depends on proper protein maturation: a homozygous missense variant that impairs PPCA dimerization markedly reduces enzymatic activity, indicating that homodimerization is required for function (PMID:40165614). Beyond its protective function, PPCA acts as a lysosomal protease that degrades LAMP2a, a rate-limiting component of chaperone-mediated autophagy, thereby coupling CTSA expression levels to autophagic flux (PMID:33255835). The CTSA gene maps to human chromosome 20q and its mouse homologue is biallelically expressed without parental imprinting (PMID:2071143, PMID:7959780).

1. 1991 High

   Before functional characterization, the chromosomal position of the protective protein gene was unknown; mapping it established the human locus and a foundation for disease-gene linkage.

   Evidence FISH mapping with cDNA and genomic probes on lymphocyte chromosome spreads

   PMID:2071143

   Open questions at the time

   • Does not address the protein's biochemical function
   • No mutation or phenotype data
2. 1994 Medium

   It was unclear whether the gene was subject to genomic imprinting; allelic expression analysis showed biallelic expression, ruling out imprinting as a regulatory layer.

   Evidence Linkage analysis and RT-PCR of allelic expression in mouse crosses with maternal/paternal chromosome imbalances

   PMID:7959780

   Open questions at the time

   • Mouse data; human imprinting status not directly tested in this finding
   • No mechanistic link to enzyme protection
3. 2013 High

   The disease mechanism of galactosialidosis was resolved by establishing that CTSA loss causes secondary deficiency of both GLB1 and NEU1, defining PPCA as a protector of these enzymes' stability.

   Evidence CTSA mutation analysis in galactosialidosis patients with computational prediction and review of biochemical consequences

   PMID:23915561

   Open questions at the time

   • Molecular basis of how PPCA physically protects GLB1/NEU1 not detailed here
   • Does not address other PPCA substrates or roles
4. 2019 Medium

   The requirement of PPCA for partner enzyme activity was confirmed directly in patient cells rather than inferred, by measuring impaired β-galactosidase and neuraminidase activity in fibroblasts carrying CTSA mutations.

   Evidence Enzymatic assays in cultured patient skin fibroblasts with Sanger-confirmed CTSA mutations

   PMID:31044084

   Open questions at the time

   • Single patient/single lab
   • Does not resolve which residues mediate enzyme protection
5. 2020 Medium

   A protective function did not explain whether PPCA itself acts proteolytically; CTSA was shown to degrade LAMP2a in lysosomes, linking it to regulation of chaperone-mediated autophagy.

   Evidence Western blot, RT-PCR, immunocytochemistry and lysosomal fractionation in leptin-treated canine mammary adenocarcinoma cells

   PMID:33255835

   Open questions at the time

   • Demonstrated in a canine cancer cell line
   • Direct proteolysis of LAMP2a by PPCA not reconstituted biochemically
   • Generality across human tissues unestablished
6. 2025 Medium

   How specific missense mutations abolish PPCA function was addressed by showing a p.Gln436Arg variant impairs dimerization, establishing homodimerization as a requirement for maturation and activity.

   Evidence In vitro functional analysis and enzymatic assay of an exome-identified CTSA variant

   PMID:40165614

   Open questions at the time

   • Single variant, single study
   • Structural basis of dimerization defect not resolved
   • Link between dimerization and enzyme-protection function not directly tested

• The molecular interface by which PPCA physically associates with and protects GLB1 and NEU1, and the structural relationship between its protective and proteolytic functions, remain unresolved.
• No structural model of the PPCA-GLB1-NEU1 complex in the corpus
• Direct substrate repertoire of PPCA protease activity incompletely defined