Identification and characterization of novel mutations of the aspartoacylase gene in non-Jewish patients with Canavan disease

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dc.contributor.authorZeng, B. J.
dc.contributor.authorWang, Z. H.
dc.contributor.authorRibeiro, L. A.
dc.contributor.authorLeone, P.
dc.contributor.authorDe Gaspari, R.
dc.contributor.authorKim, S. J.
dc.contributor.authorRaghavan, S.
dc.contributor.authorOng, E.
dc.contributor.authorPastores, G. M.
dc.contributor.authorKolodny, E. H.
dc.contributor.institutionNYU
dc.contributor.institutionUniversidade Estadual Paulista (Unesp)
dc.contributor.institutionUniv Med & Dent New Jersey
dc.date.accessioned2014-05-20T15:20:42Z
dc.date.available2014-05-20T15:20:42Z
dc.date.issued2002-11-01
dc.description.abstractCanavan disease, an inherited leukodystrophy, is caused by mutations in the aspartoacylase (ASPA) gene. It is most common among children of Ashkenazi Jewish descent but has been diagnosed in many diverse ethnic groups. Two mutations comprise the majority of mutant alleles in Jewish patients, while mutations in the ASPA gene among non-Jewish patients are different and more diverse. In the present study, the ASPA gene was analysed in 22 unrelated non-Jewish patients with Canavan disease, and 24 different mutations were found. of these,14 are novel, including five missense mutations (E24G, D68A, D249V, C152W, H244R), two nonsense mutations (Q184X, E214X), three deletions (923delT, 33del13, 244delA), one insertion mutation (698insC), two sequence variations in one allele ([10T>G; 11insG]), an elimination of the stop codon (941A>G, TAG-->TGG, X314W), and one splice acceptor site mutation (IVS1 - 2A>T). The E24G mutation resulted in substitution of an invariable amino acid residue (Glu) in the first esterase catalytic domain consensus sequence. The IVS1 - 2A>T mutation caused the retention of 40 nucleotides of intron 1 upstream of exon 2. The results of transient expression of the mutant ASPA cDNA containing these mutations in COS-7 cells and assays for ASPA activity of patient fibroblasts indicated that these mutations were responsible for the enzyme deficiency. In addition, patients with the novel D249V mutation manifested clinically at birth and died early. Also, patients with certain other novel mutations, including C152W, E214X, X314W, and frameshift mutations in both alleles, developed clinical manifestations at an earlier age than in classical Canavan disease.en
dc.description.affiliationNYU, Sch Med, Dept Neurol, New York, NY 10016 USA
dc.description.affiliationSão Paulo State Univ, Dept Genet, São Paulo, Brazil
dc.description.affiliationUniv Med & Dent New Jersey, Dept Surg, Div Neurosurg, Camden, NJ USA
dc.description.affiliationUnespSão Paulo State Univ, Dept Genet, São Paulo, Brazil
dc.format.extent557-570
dc.identifierhttp://dx.doi.org/10.1023/A:1022091223498
dc.identifier.citationJournal of Inherited Metabolic Disease. Dordrecht: Kluwer Academic Publ, v. 25, n. 7, p. 557-570, 2002.
dc.identifier.doi10.1023/A:1022091223498
dc.identifier.issn0141-8955
dc.identifier.urihttp://hdl.handle.net/11449/31942
dc.identifier.wosWOS:000180562300003
dc.language.isoeng
dc.publisherKluwer Academic Publ
dc.relation.ispartofJournal of Inherited Metabolic Disease
dc.relation.ispartofjcr4.092
dc.relation.ispartofsjr1,668
dc.rights.accessRightsAcesso restrito
dc.sourceWeb of Science
dc.titleIdentification and characterization of novel mutations of the aspartoacylase gene in non-Jewish patients with Canavan diseaseen
dc.typeArtigo
dcterms.licensehttp://www.springer.com/open+access/authors+rights
dcterms.rightsHolderKluwer Academic Publ

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