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

TY - JOUR

T1 - Indentification and characterization of novel mutations of the aspartoacylase gene in non-Jewish patients with Canavan disease

AU - Zeng, B. J.

AU - Wang, Z. H.

AU - Ribeiro, L. A.

AU - Leone, P.

AU - De Gasperi, R.

AU - Kim, S. J.

AU - Raghavan, S.

AU - Ong, E.

AU - Pastores, G. M.

AU - Kolodny, E. H.

N1 - Funding Information: We are grateful to the many patients included in this study, and to their families and physicians for their cooperation. We thank Mrs Pamela Lenz and Dr Natalie Barnett for their assistance in obtaining clinical information on the patients, and Mr Michel Naum for his assistance in the aspartoacylase enzyme assay. This study was supported by grants from the Morris and Alma Schapiro Foundation, the Margaret Enoch Fund and the Freddy Toft Memorial Fund.

PY - 2002/11

Y1 - 2002/11

N2 - Canavan 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.

AB - Canavan 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.

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U2 - 10.1023/A:1022091223498

DO - 10.1023/A:1022091223498

M3 - Review article

C2 - 12638939

SN - 0141-8955

VL - 25

SP - 557

EP - 570

JO - Journal of Inherited Metabolic Disease

JF - Journal of Inherited Metabolic Disease

IS - 7

ER -