Alternative titles; symbols
HGNC Approved Gene Symbol: ASPA
SNOMEDCT: 80544005; ICD10CM: E75.28;
Cytogenetic location: 17p13.2 Genomic coordinates (GRCh38) : 17:3,474,110-3,503,405 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 17p13.2 | Canavan disease | 271900 | Autosomal recessive | 3 |
Aspartoacylase (EC 3.5.1.15), also called aminoacylase-2, is an enzyme that hydrolyzes N-acetyl-L-aspartic acid (NAA) to aspartate and acetate.
Aminoacylase-1 (ACY1; 104620) cleaves acylated L-amino acids, except L-aspartate, into L-amino acids and an acyl group.
Kaul et al. (1993) used a bovine ASPA cDNA to isolate a partial human cDNA, which was then used to screen lung and kidney cDNA libraries for the assembly of a full-length ASPA cDNA. Human ASPA encodes a deduced 313-amino acid protein with a molecular mass of 36 kD. It shares 92% sequence identity with the bovine protein and contains 1 potential N-glycosylation site and 5 phosphorylation sites. Northern blot analysis revealed a single 1.44-kb transcript in liver and an additional 5.4-kb transcript in other tissues tested. Expression of both transcripts was highest in skeletal muscle, followed by kidney and brain. Kaul et al. (1993) showed that the isolated ASPA cDNA expressed aspartoacylase activity in bacteria.
Kaul et al. (1994) found that human ASPA coding sequences cross-hybridized with genomic DNA from yeast, chicken, rabbit, cow, dog, mouse, rat, and monkey, suggesting conservation during evolution.
Kaul et al. (1994) determined the genomic organization of the human ASPA gene and found that it contains 6 exons.
By Southern blot analysis of genomic DNA from human/mouse somatic cell hybrid cell lines, Kaul et al. (1994) localized the ASPA gene to human chromosome 17. They refined the localization to 17pter-p13 by fluorescence in situ hybridization.
Stumpf (2019) mapped the ASPA gene to chromosome 17p13.2 based on an alignment of the ASPA sequence (GenBank BC029128.1) with the genomic sequence (GRCh38).
On examination of the temporal bone in 2 sibs with Canavan disease (271900), which is caused by deficiency of ASPA, Ishiyama et al. (2003) found bilateral absence of the organ of Corti as well as absence of supporting cells and hair cells. The authors suggested a role for ASPA in the neurodevelopment of the organ of Corti.
In affected members of 3 pedigrees with Canavan disease (271900), Kaul et al. (1993) identified a point mutation in the ASPA gene (E285A; 608034.0001). The same mutation was found in 85% of 34 Canavan alleles from patients of Ashkenazi Jewish descent.
Kaul et al. (1994) reported mutation analysis of the ASPA gene in 64 probands with Canavan disease. Of the 128 unrelated Canavan chromosomes analyzed, 88 were from probands of Ashkenazi Jewish descent. The E285A mutation accounted for 82.9% of chromosomes in this population, followed by the Y231X mutation (608034.0005) (14.8%) and a splice site mutation (1.1%). The 3 mutations accounted for 98.8% of the Canavan chromosomes of Ashkenazi Jewish origin. An A305E mutation (608034.0003) was found exclusively in non-Jewish probands of European descent and constituted 60% of the 40 mutant chromosomes from this population. The predominant occurrence of certain mutations suggested a founder effect. The authors noted that more than one mutation is relatively common in the Ashkenazi Jewish population as is the case also with Tay-Sachs disease and Gaucher disease.
Shaag et al. (1995) found a variety of mutations in the ACY2 gene in non-Jewish patients with Canavan disease. In 19 non-Jewish patients they found 4 point mutations, 4 deletion mutations, and 1 exon skip. Mutations were identified in 31 of the 38 alleles in the 19 non-Jewish patients, representing an overall detection rate of 81.6%. All 9 mutations identified in non-Jewish patients resided in exons 4-6 of the ACY2 gene.
Kaul et al. (1996) identified 8 novel mutations among 25 unrelated non-Jewish patients with Canavan disease. These 8 and 3 previously characterized mutations accounted for 40 of the 50 mutant chromosomes. The A305E mutation accounted for 48% (24 of 50) of mutant chromosomes in patients of western European descent, whereas each of the 2 predominant Jewish mutations, E285A and Y231X, accounted for only a single mutant chromosome. The 8 novel mutations identified included 1- and 4-bp deletions (608034.0006, 608034.0007) and 6 missense mutations. Single-base changes leading to missense mutations were identified in patients from Turkey, the Netherlands, Germany, Ireland, and Canada. Kaul et al. (1996) described a PCR-based protocol for introducing mutations into wildtype cDNA. In vitro expression of mutant cDNA clones demonstrated that all of these mutations led to deficiency of aspartoacylase and should therefore result in Canavan disease.
As summarized by Sistermans et al. (2000), 2 mutations account for about 98% of the alleles of Ashkenazi Jewish patients, in which population the disease is highly prevalent: E285A and Y231X. In non-Jewish patients of European origin, the A305E mutation accounts for 50% of alleles. Sistermans et al. (2000) described mutation analysis in 17 European non-Jewish patients. They found 10 different mutations of which 4 were novel. An in-frame deletion of exon 4 of the ASPA gene (608034.0009) appeared to be a founder mutation in Turkish patients.
Feigenbaum et al. (2004) developed a novel molecular assay using multiplex fluorescent allele-specific PCR to test for the 3 most common mutations causing Canavan disease in the Ashkenazi Jewish population: E285A, Y231X, and A305E. Screening 1,423 Ashkenazi Jewish individuals in Toronto, the authors found 25 carriers, yielding a carrier rate of 1:57. Feigenbaum et al. (2004) noted that in all E285A carriers the 854C mutation was in disequilibrium with a T polymorphism at the site of the 693C-A mutation (Y231X), indicating a founder chromosome for the 854A-C mutation in the Ashkenazi Jewish population.
N-acetyl-L-aspartic acid contributes acetyl groups for the synthesis of lipids, which are incorporated into myelin. Madhavarao et al. (2005) found that Aspa-null mice had a 30% decrease in total myelin lipids and severely decreased levels of acetate in the brain at the time of peak postnatal CNS myelination compared to wildtype mice. However, acetate levels in liver and kidney were normal, suggesting that acetate derived from ASPA cleavage of NAA is a major source of free acetate in the brain. Analysis of white matter lipid composition from a patient with Canavan disease caused by the ASPA E285A mutation (608034.0001) showed a significant reduction in complex glycolipids comigrating with cerebroside and sulfatide. Madhavarao et al. (2005) hypothesized that mutations in the ASPA gene cause a deficiency of acetate, which results in decreased synthesis of myelin-related fatty acids and myelin. These changes impair CNS development and lead to white matter degeneration seen in Canavan disease.
Wang et al. (2021) found that homozygous knockout of the sodium-dependent dicarboxylate transporter Slc13a3 (606411) in mice with Canavan disease normalized their brain NAA, increased their body weight, improved rotarod performance, and prevented cerebellar and thalamic vacuolation. Heterozygous Slc13a3 deletion in Canavan disease mice also suppressed brain NAA elevation, enhanced accelerating rotarod performance, and partly prevented cerebellar, but not thalamic, vacuolation.
In affected patients with Canavan disease (271900), Kaul et al. (1993) identified an 854A-C transversion in the ASPA gene, resulting in a glu285-to-ala (E285A) substitution predicted to be part of the catalytic domain of aspartoacylase. The same mutation was found in 29 of 34 alleles from a sample of 17 unrelated pedigrees of Ashkenazi Jewish descent. Of the 17 probands, 12 were found to be homozygous for the mutation and 5 were compound heterozygotes, the mutation on the second Canavan allele remaining to be determined. The authors noted that the findings suggested a founder effect of this mutation in the Jewish population.
In 18 patients from Israel with Canavan disease, Elpeleg et al. (1994) found the E285A change in the homozygous state. All were Israeli Ashkenazi Jews. Among 879 healthy Israeli Ashkenazi Jews, 15 heterozygotes were found, representing a carrier rate of 1 in 59 and suggesting that a screening for the mutation is warranted among couples of particular ethnic background.
In an Arab child with Canavan disease (271900), 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.
In patients with Canavan disease (271900), Kaul et al. (1994) identified a 914C-A change in exon 6 of the ASPA gene, resulting in an ala305-to-glu (A305E) substitution. The mutation was found exclusively in non-Jewish patients and constituted 60% of the 40 chromosomes analyzed. Expression of the mutation in COS-1 cells showed a complete loss of ASPA enzyme activity.
Shaag et al. (1995) found the A305E mutation in 15 of 38 (39.5%) mutant alleles in 19 non-Jewish patients. This distribution was pan-European, suggesting that it is the most ancient mutation. Patients with the mutation were of Greek, Polish, Danish, French, Spanish, Italian, and British origin. Homozygosity for the A305E mutation was identified in patients with both the severe and the mild forms of Canavan disease.
In 3 Gypsy patients with Canavan disease (271900), Shaag et al. (1995) found homozygosity for a cys218-to-ter (C218X) mutation caused by a TGC-to-TGA transversion.
In Ashkenazi Jewish patients with Canavan disease (271900), Kaul et al. (1994) identified a 693C-A nonsense mutation in exon 5 of the ASPA gene (Y231X). They also identified a silent polymorphism, 693C/T. Expression of the mutation in COS-1 cells showed a complete loss of ASPA enzyme activity.
Among Ashkenazi Jewish patients with Canavan disease, Kaul et al. (1996) found that the G285A missense mutation (608034.0001) and the Y231X nonsense mutation accounted for 97% of 104 mutant chromosomes examined.
Propheta et al. (1998) found a sequence polymorphism at nucleotide 693 (693C/T); the relative frequency of the 693C and the 693T alleles in the tested population was 0.75 and 0.25, respectively. The practical significance was that the 693T allele yielded results like those of the 693A mutation in some test systems.
Kaul et al. (1996) found heterozygosity for a 4-bp deletion beginning with 876A in 3 independent (presumably unrelated) Canavan (271900) patients from England.
In the only known patient of African American origin with Canavan disease (271900), Kaul et al. (1996) demonstrated homozygosity for deletion of a T at position 32 in the sequence of the ASPA cDNA.
In a girl with Canavan disease (271900) born to first-cousin Turkish parents, Rady et al. (1999) identified a tyr231-to-cys (Y231C) mutation in the ASPA gene.
Sistermans et al. (2000) found an in-frame deletion of exon 4 of the ASPA gene in all 5 alleles in patients of Turkish origin with Canavan disease (271900). Two Turkish patients were homozygous for the deletion; a patient of mixed Dutch and Turkish ancestry was heterozygous for the mutation.
In a German patient with Canavan disease (271900), Zeng et al. (2002) identified an A-to-G transition at nucleotide 71 of the ASPA gene resulting in a glutamic acid-to-glycine substitution at codon 24 (E24G). This change occurred at an invariable glutamic acid position in the first esterase catalytic domain consensus sequence.
In 2 British nonconsanguineous patients with Canavan disease (271900), Zeng et al. (2002) identified an A-to-T transversion at nucleotide 746 of the ASPA gene resulting in an aspartate-to-valine substitution at codon 249 (D249V). Both patients had severe clinical course with onset in the neonatal period. In vitro mutagenesis and expression of mutant cDNA containing this mutation showed no ASPA activity in COS-7 cells.
In 2 sisters with a mild form of Canavan disease (271900), Janson et al. (2006) identified compound heterozygosity for 2 mutations in the ASPA gene: a 212G-A transition resulting in an arg71-to-his (R71H) substitution and A305E (608034.0003). They presented at ages 50 and 19 months, respectively, with developmental delay, but without macrocephaly, hypotonia, spasticity, or seizures. The older child had mild cognitive and social impairment, whereas the infant showed age-appropriate language and behavior. In vitro studies showed severely deficient ASPA enzyme activity, but cerebral NAA levels in both patients were significantly less than expected for classic Canavan disease.
Velinov et al. (2008) reported a 28-month-old girl with a mild form of Canavan disease associated with homozygosity for the R71H mutation. The parents were not related and originated from Ecuador. The child showed mild motor and speech delay at age 9 months and developed symmetric hyperintensities in the basal ganglia at age 18 months. She walked at age 19 months and spoke about 20 words at 25 months. She did not have macrocephaly or seizures. NAA levels were about 15 times greater than normal but lower than that observed in classic Canavan disease. Velinov et al. (2008) concluded that the R71H mutation is associated with a milder form of the disorder.
Elpeleg, O. N., Anikster, Y., Barash, V., Branski, D., Shaag, A. The frequency of the C854 mutation in the aspartoacylase gene in Ashkenazi Jews in Israel. Am. J. Hum. Genet. 55: 287-288, 1994. [PubMed: 8037206]
Feigenbaum, A., Moore, R., Clarke, J., Hewson, S., Chitayat, D., Ray, P. N., Stockley, T. L. Canavan disease: carrier-frequency determination in the Ashkenazi Jewish population and development of a novel molecular diagnostic assay. Am. J. Med. Genet. 124A: 142-147, 2004. [PubMed: 14699612] [Full Text: https://doi.org/10.1002/ajmg.a.20334]
Ishiyama, G., Lopez, I., Baloh, R. W., Ishiyama, A. Canavan's leukodystrophy is associated with defects in cochlear neurodevelopment and deafness. Neurology 60: 1702-1704, 2003. [PubMed: 12771274] [Full Text: https://doi.org/10.1212/01.wnl.0000065893.60879.d3]
Janson, C. G., Kolodny, E. H., Zeng, B.-J., Raghavan, S., Pastores, G., Torres, P., Assadi, M., McPhee, S., Goldfarb, O., Saslow, B., Freese, A., Wang, D. J., Bilaniuk, L., Shera, D., Leone, P. Mild-onset presentation of Canavan's disease associated with novel G212A point mutation in aspartoacylase gene. Ann. Neurol. 59: 428-431, 2006. [PubMed: 16437572] [Full Text: https://doi.org/10.1002/ana.20787]
Kaul, R., Balamurugan, K., Gao, G. P., Matalon, R. Canavan disease: genomic organization and localization of human ASPA to 17p13-ter and conservation of the ASPA gene during evolution. Genomics 21: 364-370, 1994. [PubMed: 8088831] [Full Text: https://doi.org/10.1006/geno.1994.1278]
Kaul, R., Gao, G. P., Aloya, M., Balamurugan, K., Petrosky, A., Michals, K., Matalon, R. Canavan disease: mutations among Jewish and non-Jewish patients. Am. J. Hum. Genet. 55: 34-41, 1994. [PubMed: 8023850]
Kaul, R., Gao, G. P., Balamurugan, K., Matalon, R. Cloning of the human aspartoacylase cDNA and a common missense mutation in Canavan disease. Nature Genet. 5: 118-123, 1993. [PubMed: 8252036] [Full Text: https://doi.org/10.1038/ng1093-118]
Kaul, R., Gao, G. P., Matalon, R., Aloya, M., Su, Q., Jin, M., Johnson, A. B., Schutgens, R. B. H., Clarke, J. T. R. Identification and expression of eight novel mutations among non-Jewish patients with Canavan disease. Am. J. Hum. Genet. 59: 95-102, 1996. [PubMed: 8659549]
Kaul, R., Gao, G. P., Michals, K., Whelan, D. T., Levin, S., Matalon, R. Novel (cys152-to-arg) missense mutation in an Arab patient with Canavan disease. Hum. Mutat. 5: 269-271, 1995. [PubMed: 7599639] [Full Text: https://doi.org/10.1002/humu.1380050313]
Madhavarao, C. N., Arun, P., Moffett, J. R., Szucs, S., Surendran, S., Matalon, R., Garbern J., Hristova, D., Johnson, A., Jiang, W., Namboodiri, M. A. A. Defective N-acetylaspartate catabolism reduces brain acetate levels and myelin lipid synthesis in Canavan's disease. Proc. Nat. Acad. Sci. 102: 5221-5226, 2005. [PubMed: 15784740] [Full Text: https://doi.org/10.1073/pnas.0409184102]
Propheta, O., Magal, N., Shohat, M., Eyal, N., Navot, N., Horowitz, M. A benign polymorphism in the aspartoacylase gene may cause misinterpretation of Canavan gene testing. Europ. J. Hum. Genet. 6: 635-637, 1998. [PubMed: 9887384] [Full Text: https://doi.org/10.1038/sj.ejhg.5200225]
Rady, P. L., Vargas, T., Tyring, S. K., Matalon, R., Langenbeck, U. Novel missense mutation (Y231C) in a Turkish patient with Canavan disease. (Letter) Am. J. Med. Genet. 87: 273-275, 1999. [PubMed: 10564886] [Full Text: https://doi.org/10.1002/(sici)1096-8628(19991126)87:3<273::aid-ajmg17>3.0.co;2-o]
Shaag, A., Anikster, Y., Christensen, E., Glustein, J. Z., Fois, A., Michelakakis, H., Nigro, F., Pronicka, E., Ribes, A., Zabot, M. T., Elpeleg, O. N. The molecular basis of Canavan (aspartoacylase deficiency) disease in European non-Jewish patients. Am. J. Hum. Genet. 57: 572-580, 1995. [PubMed: 7668285]
Sistermans, E. A., de Coo, R. F. M., van Beerendonk, H. M., Poll-The, B. T., Kleijer, W. J., van Oost, B. A. Mutation detection in the aspartoacylase gene in 17 patients with Canavan disease: four new mutations in the non-Jewish population. Europ. J. Hum. Genet. 8: 557-560, 2000. [PubMed: 10909858] [Full Text: https://doi.org/10.1038/sj.ejhg.5200477]
Stumpf, A. M. Personal Communication. Baltimore, Md. 12/03/2019.
Velinov, M., Zellers, N., Styles, J., Wisniewski, K. Homozygosity for mutation G212A of the gene for aspartoacylase is associated with atypical form of Canavan's disease. (Letter) Clin. Genet. 73: 288-289, 2008. [PubMed: 18070137] [Full Text: https://doi.org/10.1111/j.1399-0004.2007.00934.x]
Wang, Y., Hull, V., Sternbach, S., Popovich, B., Burns, T., McDonough, J., Guo, F., Pleasure, D. Ablating the transporter sodium-dependent dicarboxylate transporter 3 prevents leukodystrophy in Canavan disease mice. Ann. Neurol. 90: 845-850, 2021. [PubMed: 34498299] [Full Text: https://doi.org/10.1002/ana.26211]
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. Identification and characterization of novel mutations of the aspartoacylase gene in non-Jewish patients with Canavan disease. J. Inherit. Metab. Dis. 25: 557-570, 2002. [PubMed: 12638939] [Full Text: https://doi.org/10.1023/a:1022091223498]