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

• Published in: Journal of inherited metabolic disease 2002-11, Vol.25 (7), p.557-570
• Main Authors: Zeng, B. J., Wang, Z. H., Ribeiro, L. A., Leone, P., De Gasperi, R., Kim, S. J., Raghavan, S., Ong, E., Pastores, G. M., Kolodny, E. H.
• Format: Article
• Language: English
• Subjects: Amidohydrolases - genetics; Base Sequence; Biological and medical sciences; Canavan Disease - enzymology; Canavan Disease - genetics; Carbohydrates (enzymatic deficiencies). Glycogenosis; Codon, Nonsense; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; DNA Mutational Analysis; DNA, Complementary - genetics; Errors of metabolism; Exons; Genotype; Humans; Infant; Infant, Newborn; Jews - genetics; Lipids (lysosomal enzyme disorders, storage diseases); Medical sciences; Metabolic diseases; Mutation; Mutation, Missense; Neurology; Phenotype; Sequence Deletion
• ISSN: 0141-8955; 1573-2665
• DOI: 10.1023/A:1022091223498

Canavan disease, an inherited leukodystrophy, is caused by mutationsin 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.