Galactosialidosis: Review and analysis of CTSA gene mutations

Anna Caciotti, Serena Catarzi, Rodolfo Tonin, Licia Lugli, Carmen Rodriguez Perez, Helen Michelakakis, Irene Mavridou, Maria Alice Donati, Renzo Guerrini, Alessandra D'Azzo, Amelia Morrone

Research output: Contribution to journalArticle

Abstract

Background: Mutations in the CTSA gene, that encodes the protective protein/cathepsin A or PPCA, lead to the secondary deficiency of β-galactosidase (GLB1) and neuraminidase 1 (NEU1), causing the lysosomal storage disorder galactosialidosis (GS). Few clinical cases of GS have been reported in the literature, the majority of them belonging to the juvenile/adult group of patients. Methods. The correct nomenclature of mutations for this gene is discussed through the analysis of the three PPCA/CTSA isoforms available in the GenBank database. Phenotype-genotype correlation has been assessed by computational analysis and review of previously reported single amino acid substitutions. Results: We report the clinical and mutational analyses of four cases with the rare infantile form of GS. We identified three novel nucleotide changes, two of them resulting in the missense mutations, c.347A>G (p.His116Arg), c.775T>C (p.Cys259Arg), and the third, c.1216C>T, resulting in the p.Gln406* stop codon, a type of mutation identified for the first time in GS. An Italian founder effect of the c.114delG mutation can be suggested according to the origin of the only three patients carrying this mutation reported here and in the literature. Conclusions: In early reports mutations nomenclature was selected according to all CTSA isoforms (three different isoforms), thus generating a lot of confusion. In order to assist physicians in the interpretation of detected mutations, we mark the correct nomenclature for CTSA mutations. The complexity of pathology caused by the multifunctions of CTSA, and the very low numbers of mutations (only 23 overall) in relation to the length of the CTSA gene are discussed.In addition, the in silico functional predictions of all reported missense mutations allowed us to closely predict the early infantile, late infantile and juvenile phenotypes, also disclosing different degrees of severity in the juvenile phenotype.

Original languageEnglish
Article number114
JournalOrphanet Journal of Rare Diseases
Volume8
Issue number1
DOIs
Publication statusPublished - 2013

ASJC Scopus subject areas

  • Medicine(all)
  • Genetics(clinical)
  • Pharmacology (medical)

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    Caciotti, A., Catarzi, S., Tonin, R., Lugli, L., Perez, C. R., Michelakakis, H., Mavridou, I., Donati, M. A., Guerrini, R., D'Azzo, A., & Morrone, A. (2013). Galactosialidosis: Review and analysis of CTSA gene mutations. Orphanet Journal of Rare Diseases, 8(1), [114]. https://doi.org/10.1186/1750-1172-8-114