The ASPA gene codes for the hydrolytic enzyme called aspartoacylase. This enzyme catalyzes the deacetylation of N-acetylaspartic acid (NAA) in the oligodendrocytes in the central nervous system (CNS) to produce L-aspartate and acetate. The acetyl groups of NAA are used for the synthesis of lipid, which in turn are incorporated into myelin. The deficiency or ineffectively of this enzyme interferes with the normal hydrolysis of NAA and, thus, the availability of the acetyl group required for synthesis of the lipid portion of myelin. This would lead to impaired normal myelination, spongy degeneration of the white matter of the brain, and abnormal accumulation of NAA in brain and its excessive excretion in urine. In addition, it has been proposed that excess NAA leads to osmotic dysregulation because it has been proposed that NAA acts as an organic osmolyte that removes excess water from neurons by acting as a molecular water pump. Mutations in the ASPA gene lead to all these effects which are also seen in Canavan disease.
The ASPA gene is located on the short arm of chromosome 17 at 17pter-p13 and spans approximately 29 kb of genomic DNA with a coding sequence consisting of six exons. The ASPA protein consists of 313 amino acids weighing approximately 36 KDa. The ASPA-coding sequence is highly conserved across species during evolution. ASPA is strongly expressed not only in the oligodendrocytes in the nervous tissue, but also in other tissues, such as kidney, but the only known substrate, NAA, is present predominantly in the nervous system. During early postnatal central nervous system (CNS) development, the ASPA gene expression in oligodendrocytes is increased along with increased production of its substrate (NAA) in neurons. NAA is transported from neurons to the cytoplasm of oligodendrocytes, where ASPA can perform its normal function.
To date, more than 55 mutations have been identified in the ASPA gene leading to Canavan disease. The majority of patients with Canavan disease are from an Ashkenazi Jewish background with two founder mutations (E285A) and (Y231X). These two mutations together account for 98% of the mutant alleles in Ashkenazi Jewish Canavan patients, whereas they account only 3% in non-Jewish patients. However, mutations in the ASPA gene among non-Jewish patients are different and more diverse with the mutation (A305E) seen more frequently among non-Jewish patients of European descent.
Masri and Hamamy (2006) reported the first cases of Canavan disease from Jordan. The proband was a one-month old infant, born to healthy consanguineous parents with an uneventful antenatal history. Masri and Hamamy (2006) performed a mutation analysis of the ASPA gene, which revealed a rare mutation, 79G-to-A (G27R), in exon 1 of the gene.
Kaya et al. (2008) undertook mutation analysis of five unrelated patients with Canavan Disease from Saudi Arabia. Direct sequencing of the ASPA gene indentified a homozygous splice donor site mutation (IVS4+1G>T) in the first patient and a missense mutation (p.G27R) in the second. For the remaining patients, a combination of MLPA assay, long-PCR and arrayCGH was used. This enabled the identification of a novel deletion in two of the patients, extending from introns 2 and 3, comprising the full exon 3 and extending 3346 bp. This deletion is supposed to have resulted in an enzyme having affected zinc coordination, substrate binding, and local unfolding problems. The last patient was found to have a previously reported large 92 kb deletion starting 7.16 kb upstream of the ASPA start site and continuing on to the 3' sequence of the adjacent TRPV3 gene. Kaya et al. (2008) conducted a genome wide expression profiling on RNA isolated from cultured fibroblasts from two of these Saudi patients. Compared with normal fibroblasts, 1440 genes were commonly significantly modulated. Many of these genes had earlier been identified in mouse Canavan Disease models, and included genes involved in apoptosis/antiapoptosis, cell growth, cell signal transduction, cell death, and inflammatory pathways.
In an Arab child with Canavan disease, Kaul et al. (1995) identified a 454T-C transition in the ASPA gene, resulting in a cys152-to-arg (C152R) amino acid substitution. This was the second missense mutation and the fifth mutation of any type to be described for the ASPA gene.
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