title: Molecular analysis of ARSA and PSAP genes in twenty-one Italian patients with metachromatic leukodystrophy: identification and functional characterization of 11 novel ARSA alleles.
abstract: Metachromatic leukodystrophy (MLD), the demyelinating disorder resulting from impaired sulfatide catabolism, is caused by allelic mutations of the Arylsulfatase A (ARSA) locus except for extremely rare cases of Saposin-B (Sap-B) deficiency. We characterized twenty-one unrelated Italian patients among which seventeen were due to ARSA activity deficiency and 4 others resulted from Saposin-B defect. Overall, we found 20 different mutant ARSA alleles and 2 different Sap-B alleles. The eleven new ARSA alleles (c.53C>A; c.88G>C; c.372G>A; c.409_411delCCC; c.634G>C; [c.650G>A;c.1108C>T]; c.845A>G; c.906G>C; c.919G>T; c.1102-3C>G; c.1126T>A) were functionally characterized and the novel amino acid changes were also modelled into the three-dimensional structure. The present study is aimed at providing a broader picture of the molecular basis of MLD in the Italian population. It also emphasizes the importance of a comprehensive evaluation in MLD diagnosis including biochemical, enzymatic and molecular investigations.
authors.affiliation: Laboratorio Diagnosi Pre-Postnatale Malattie Metaboliche, Genova, Italy.
authors.forename: Serena
authors.initials: S
authors.lastname: Grossi
authors.forename: Stefano
authors.initials: S
authors.lastname: Regis
authors.forename: Camillo
authors.initials: C
authors.lastname: Rosano
authors.forename: Fabio
authors.initials: F
authors.lastname: Corsolini
authors.forename: Graziella
authors.initials: G
authors.lastname: Uziel
authors.forename: Maria
authors.initials: M
authors.lastname: Sessa
authors.forename: Maja
authors.initials: M
authors.lastname: Di Rocco
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Parenti
authors.forename: Federica
authors.initials: F
authors.lastname: Deodato
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Leuzzi
authors.forename: Roberta
authors.initials: R
authors.lastname: Biancheri
authors.forename: Mirella
authors.initials: M
authors.lastname: Filocamo
mesh_terms: D000328:Adult; D000483:Alleles; D000818:Animals; D019556:COS Cells; D020134:Catalytic Domain; D002553:Cerebroside-Sulfatase / Q000235:genetics*; D002675:Child, Preschool; D002522:Chlorocebus aethiops; D004252:DNA Mutational Analysis; D006801:Humans; D007223:Infant; D007558:Italy; D007966:Leukodystrophy, Metachromatic / Q000235:genetics*; D008958:Models, Molecular; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D017434:Protein Structure, Tertiary; D049231:Saposins / Q000235:genetics*
chemical_list: C483345:PSAP protein, human; D049231:Saposins; D002553:Cerebroside-Sulfatase