title: Galactosialidosis: review and analysis of CTSA gene mutations.
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.
authors.affiliation: Laboratory for Molecular and Cell Biology, Paediatric Neurology Unit and Laboratories, Meyer Children's Hospital, Viale Pieraccini n, 24, Florence 50139, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Caciotti
authors.forename: Serena
authors.initials: S
authors.lastname: Catarzi
authors.forename: Rodolfo
authors.initials: R
authors.lastname: Tonin
authors.forename: Licia
authors.initials: L
authors.lastname: Lugli
authors.forename: Carmen Rodriguez
authors.initials: CR
authors.lastname: Perez
authors.forename: Helen
authors.initials: H
authors.lastname: Michelakakis
authors.forename: Irene
authors.initials: I
authors.lastname: Mavridou
authors.forename: Maria Alice
authors.initials: MA
authors.lastname: Donati
authors.forename: Renzo
authors.initials: R
authors.lastname: Guerrini
authors.forename: Alessandra
authors.initials: A
authors.lastname: d'Azzo
authors.forename: Amelia
authors.initials: A
authors.lastname: Morrone
mesh_terms: D043402:Cathepsin A / Q000737:chemistry / Q000235:genetics*; D019295:Computational Biology / Q000379:methods; D056726:Genetic Association Studies; D016464:Lysosomal Storage Diseases / Q000175:diagnosis / Q000235:genetics / Q000473:pathology; D009154:Mutation; D020125:Mutation, Missense; D017422:Sequence Analysis, DNA
chemical_list: C468629:CTSA protein, human; D043402:Cathepsin A
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