Alternative titles; symbols
HGNC Approved Gene Symbol: ACY1
SNOMEDCT: 709282004;
Cytogenetic location: 3p21.2 Genomic coordinates (GRCh38): 3:51,983,535-51,989,197 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 3p21.2 | Aminoacylase 1 deficiency | 609924 | Autosomal recessive | 3 |
Aminoacylase-1 (EC 3.5.1.14) is a homodimeric zinc-binding metalloenzyme. A cytosolic enzyme with a wide range of tissue expression, it cleaves acylated L-amino acids (except L-aspartate) into L-amino acids and an acyl group. L-aspartate derivatives are cleaved by aminoacylase-2 (aspartoacylase; 608034). Aminoacylase-1 is the most abundant of the aminoacylases, a class of enzymes involved in hydrolysis of N-acetylated proteins.
Using a panel of monoclonal antibodies specific for aminoacylase-1, Miller et al. (1989, 1990) isolated an ACY1 cDNA from a lambda gt11 expression library.
Cook et al. (1993) isolated an ACY1 cDNA of 1,438 bp with an open reading frame of 1,224 bp coding for a putative protein of 408 amino acids with a predicted molecular mass of 45,882 Da. Sequence analysis demonstrated no homology to previously reported cDNA or protein sequences and established ACY1 as the first member of a new family of zinc-binding enzymes. The subcellular localization of ACY1 was established to be cytosolic by flow cytometry. Southern and Northern analyses of ACY1 in SCLC cell lines failed to demonstrate any gross abnormalities of the ACY1 structural gene or instances of absent or aberrantly sized mRNA, respectively.
Ferri et al. (2014) stated that the ACY1 gene comprises 15 exons, the first of which is noncoding.
Naylor et al. (1979) developed a novel method for visualizing isozymes of cultured somatic cells after zone electrophoresis ('bioautography') and applied it in the study of interspecific cell hybrids to assign the gene for aminoacylase-1 to chromosome 3. The principle of bioautography is the visualization of an enzyme by a zone of bacterial growth that results when an auxotrophic bacterium is supplied a required product by the enzyme. Voss et al. (1980) confirmed the assignment to chromosome 3 and suggested that the most likely site of the locus is 3p21-3pter.
By studying recombinant inbred strains of mice, Naylor et al. (1982) found that aminoacylase-1 and beta-galactosidase A are 10.7 map units apart on mouse chromosome 9. Since transferrin is closely linked to these 2 loci in the mouse, they suggested that the human transferrin gene may be on chromosome 3, which is known to carry ACY1 and GLB1. Nadeau (1986) demonstrated that the mouse homologs for the human genes TF, ACY1, and GLB1 are in that order on mouse chromosome 9. He took this to mean that aminoacylase-1 and beta-galactosidase mark a chromosomal segment that has been conserved since divergence of lineages leading to man and mouse.
Using a panel of somatic cell hybrids containing fragments of chromosome 3, Miller et al. (1989, 1990) localized the gene to distal 3p21.1. An additional restriction fragment to which the probe hybridized was assigned to chromosome 18 and appeared to be expressed as an mRNA species.
Jones et al. (1991) compared this enzyme with acylpeptide hydrolase (APH; 102645), which also maps to 3p21 and shares functional features. By pulsed field gel electrophoretic (PFGE) studies, Gemmill et al. (1991) showed that ACY1 is physically linked to D3S2 within a 2.5-Mb region in 3p21.1, but DNF15S2, a marker for acylpeptide hydrolase, was shown by Boldog et al. (1989), also by PFGE studies, not to be linked to D3S2. Ginzinger et al. (1992) suggested that ACY1 (at 3p21.1) may be an 'ancestral copy' of the APH gene at 3p21.3.
Voss et al. (1980) described a method of colorimetric-enzymatic determination on electrophoresis and showed that ACY1 hydrolyzes both acetyl-methionine and acetyl-glutamate.
Whereas aminoacylase-1 normally is expressed in all nucleated human cells (it is not expressed in erythrocytes), Miller et al. (1989) found that the enzyme was undetectable in 4 of 29 small cell lung cancer (SCLC) cell lines and in 1 of 8 SCLC tumors (182280). The finding supports the hypothesis that inactivation of both alleles of specific chromosome 3p genes occurs in SCLC in a fashion analogous to RB (614041) gene inactivation in retinoblastoma (180200) and suggests that the ACY1 gene may be closely linked to the putative SCLC tumor suppressor gene.
Using a yeast 2-hybrid screen of mouse genes, Maceyka et al. (2004) identified Acy1 as a Sphk1 (603730)-interacting protein. Cotransfection of the genes into HEK293 cells showed that the 2 proteins coimmunoprecipitated. The C-terminal fragment of Acy1 inhibited, while full-length Acy1 enhanced, the effects of Sphk1 on proliferation and anti-apoptosis. Acy1 also appeared to induce redistribution of Sphk1 to the plasma membrane. The findings suggested that Acy1 that influences the cellular localization and activity of Sphk1.
A genetic polymorphism of the Acy1 enzyme was demonstrated in the mouse (Naylor et al., 1979).
Sass et al. (2006) reported 4 children with aminoacylase-1 deficiency (ACY1D; 609924) identified through organic acid analyses using gas chromatography-mass spectrometry, revealing increased urinary excretion of several N-acetylated amino acids. It was unclear whether ACY1 deficiency was related to the clinical phenotypes in the reported patients or merely represented a biochemical abnormality. The gene exhibits evolutionary conservation and is expressed in brain, liver, and kidney, suggesting a role of the enzyme in amino acid metabolism of these organs. However, the authors noted that the phenotypic variability of the patients, whose ACY1 deficiency was detected by newborn screening, did not support ACY1 deficiency as a disease.
Sass et al. (2007) identified compound heterozygous or homozygous mutations in the ACY1 gene (104620.0002; 104620.0005; 104620.0006) in 3 unrelated patients with ACY1 deficiency. R353C was the most common mutation, present in 3 of the 6 alleles.
In the offspring of consanguineous Turkish parents, residing in Germany, Sass et al. (2006) detected aminoacylase-1 deficiency (ACY1D; 609924) by the presence of N-acetylamino acids in the urine in the course of selective screening for inborn errors of metabolism. The subject's development appeared to be normal. He attended high school. He started walking at age 1 year. At age 3 years, the parents first observed muscle weakness that prompted a thorough investigation at age 11 years. During that examination the boy presented with low normal muscle tone and a shambling gait. Extensive studies revealed no significant myopathologic abnormalities. Sass et al. (2006) identified a homozygous loss-of-function mutation in the ACY1 gene predicting aberrant translation, a 2-bp insertion, 1105_1106insAC. The 2-bp insertion predicted a frameshift beginning with amino acid residue 369 (369ProfsTer46). Notably, the mutation did not lead to premature termination of translation but predicted a C-terminal mutated protein longer than the wildtype protein (408 amino acid residues) and affected the C-terminal peptidase domain. Both parents were heterozygous carriers.
In a patient with aminoacylase-1 deficiency (ACY1D; 609924), Van Coster et al. (2005) identified a homozygous 1057C-T transition in exon 14 of the ACY1 gene, resulting in an arg353-to-cys (R353C) substitution. Both parents were heterozygous for the mutation, and it was identified in the heterozygous state in 5 of 161 controls. In vitro functional expression studies showed complete absence of enzyme activity.
Sass et al. (2006) described ACY1 deficiency in the child of nonconsanguineous German parents. The boy was identified in a general neonatal screening as being biotinidase deficient (253260), for which he was given treatment with 5 mg biotin per day. Under this medication his cognitive and motor skills developed completely normally to the time of reporting at age 17 months. He was found to be homozygous for the R353C mutation. Each parent was heterozygous for the mutation. The R353C mutation was found in another patient in compound heterozygosity with another missense mutation (104620.0003). Sass et al. (2006) also found this mutation in 1 of 210 control chromosomes, consistent with this allele being a rare polymorphism or a more common mutation.
Sass et al. (2007) identified the R353C mutation in 2 additional children with ACY1 deficiency. One was homozygous for the mutation and the other compound heterozygous with R393H (104620.0006). Both patients presented at around 1 year of age with seizures. One showed complete recovery, and the other had moderate mental retardation.
Sass et al. (2006) found compound heterozygosity for 2 missense mutations of the ACY1 gene as the apparent basis of aminoacylase-1 deficiency (ACY1D; 609924) in the daughter of healthy parents of German (mother) and Italian (father) origin. One mutation in the child was R353C (104620.0002). The other was a 699A-C transversion in exon 10 that resulted in a glu233-to-asp change (E233D). At age 2 years, a neuropediatric evaluation was initiated because of moderately retarded cognitive and motor development.
In a boy with aminoacylase-1 deficiency (ACY1D; 609924), the son of consanguineous Turkish parents, Sass et al. (2006) found homozygosity for a splice site mutation in the ACY1 gene. The homozygous mutation IVS5-1G-A predicted malfunction of the acceptor splice site of exon 6, skipping of exon 6 (amino acid residues 121 to 146), and a premature stop codon. Both parents were heterozygous for this mutation. The child had been investigated because of early impaired psychomotor development characterized by markedly disturbed central coordination and low muscle tone. Cerebellar hypoplasia had been suggested prenatally by sonography. Magnetic resonance imaging of the head and spine at the age of 3 months demonstrated hypoplasia of the corpus callosum and vermis cerebelli, as well as delayed myelination of the supratentorial white matter. The lumbar spinal cord exhibited syringomyelia with a length of 3.5 cm.
In an Asian girl, born of consanguineous parents, with aminoacylase-1 deficiency (ACY1D; 609924), Sass et al. (2007) identified a homozygous 589C-T transition in the ACY1 gene, resulting in an arg197-to-trp (R197W) substitution. She was originally detected by newborn screening. At age 11 months, she presented with febrile seizures, followed by another episode of seizures 3 months later. She showed delayed speech and language development at age 4 years.
In an English girl with aminoacylase-1 deficiency (ACY1D; 609924), Sass et al. (2007) identified compound heterozygosity for 2 mutations in the ACY1 gene: a 1178G-A transition, resulting in an arg393-to-his (R393H) substitution, and the R353C mutation (104620.0002).
In a 6-year-old girl, born of consanguineous parents, with aminoacylase-1 deficiency (ACY1D; 609924) and severe neurologic impairment, Ferri et al. (2014) identified a homozygous 6-bp deletion (c.1001_1001+5_del6) involving the last nucleotide of exon 13 and the first 5 nucleotides of intron 13. PCR analysis of patient cells showed the absence of exon 13 in the mRNA, resulting in a frameshift and premature termination (Lys308GlufsTer7). Patient fibroblasts showed absent ACY1 enzymatic activity. Parental DNA was not available for segregation analysis.
Boldog, F., Erlandsson, R., Klein, G., Sumegi, J. Long-range restriction enzyme maps of DNF15S2, D3S2 and c-raf1 loci on the short arm of human chromosome 3. Cancer Genet. Cytogenet. 42: 295-306, 1989. [PubMed: 2571406] [Full Text: https://doi.org/10.1016/0165-4608(89)90098-8]
Cook, R. M., Burke, B. J., Buchhagen, D. L., Minna, J. D., Miller, Y. E. Human aminoacylase-1: cloning, sequence, and expression analysis of a chromosome 3p21 gene inactivated in small cell lung cancer. J. Biol. Chem. 268: 17010-17017, 1993. [PubMed: 8394326]
Ferri, L., Funghini, S., Fioravanti, A., Biondi, E. G., la Marca, G., Guerrini, R., Donati, M. A., Morrone, A. Aminoacylase I deficiency due to ACY1 mRNA exon skipping. Clin. Genet. 86: 367-372, 2014. [PubMed: 24117009] [Full Text: https://doi.org/10.1111/cge.12297]
Gemmill, R. M., Varella-Garcia, M., Smith, D. I., Erickson, P., Golembieski, W., Miller, Y., Coyle-Morris, J., Tommerup, N., Drabkin, H. A. A 2.5 Mb physical map within 3p21.1 spans the breakpoint associated with Greig cephalopolysyndactyly syndrome. Genomics 11: 93-102, 1991. [PubMed: 1662666] [Full Text: https://doi.org/10.1016/0888-7543(91)90105-n]
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Jones, W. M., Scaloni, A., Bossa, F., Popowicz, A. M., Schneewind, O., Manning, J. M. Genetic relationship between acylpeptide hydrolase and acylase, two hydrolytic enzymes with similar binding but different catalytic specificities. Proc. Nat. Acad. Sci. 88: 2194-2198, 1991. [PubMed: 2006156] [Full Text: https://doi.org/10.1073/pnas.88.6.2194]
Maceyka, M., Nava, V. E., Milstien, S., Spiegel, S. Aminoacylase 1 is a sphingosine kinase 1-interacting protein. FEBS Lett. 568: 30-34, 2004. [PubMed: 15196915] [Full Text: https://doi.org/10.1016/j.febslet.2004.04.093]
Miller, Y. E., Drabkin, H., Jones, C., Fisher, J. H. Aminoacylase-1: cDNA isolation, regional assignment to chromosome 3p21.1 and identification of a cross-hybridizing sequence on chromosome 18. (Abstract) Am. J. Hum. Genet. 45 (suppl.): A28 only, 1989.
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Nadeau, J. H. A chromosomal segment conserved since divergence of lineages leading to man and mouse: the gene order of aminoacylase-1, transferrin, and beta-galactosidase on mouse chromosome 9. Genet. Res. 48: 175-178, 1986. Note: Erratum: Genet. Res. 50: 77 only, 1987. [PubMed: 3106151] [Full Text: https://doi.org/10.1017/s0016672300024976]
Naylor, S. L., Elliott, R. W., Brown, J. A., Shows, T. B. Mapping of aminoacylase-1 and beta-galactosidase-A to homologous regions of human chromosome 3 and mouse chromosome 9 suggests location of additional genes. Am. J. Hum. Genet. 34: 235-244, 1982. [PubMed: 6803586]
Naylor, S. L., Shows, T. B., Klebe, R. J. Bioautographic visualization of aminoacylase-1: assignment of the structural gene ACY-1 to chromosome 3 in man. Somat. Cell Genet. 5: 11-21, 1979. [PubMed: 373141] [Full Text: https://doi.org/10.1007/BF01538782]
Sass, J. O., Mohr, V., Olbrich, H., Engelke, U., Horvath, J., Fliegauf, M., Loges, N. T., Schweitzer-Krantz, S., Moebus, R., Weiler, P., Kispert, A., Superti-Furga, A., Wevers, R. A., Omran, H. Mutations in ACY1, the gene encoding aminoacylase 1, cause a novel inborn error of metabolism. Am. J. Hum. Genet. 78: 401-409, 2006. [PubMed: 16465618] [Full Text: https://doi.org/10.1086/500563]
Sass, J. O., Olbrich, H., Mohr, V., Hart, C., Woldseth, B., Krywawych, S., Bjurulf, B., Lakhani, P. K., Buchdahl, R. M., Omran, H. Neurological findings in aminoacylase 1 deficiency. Neurology 68: 2151-2153, 2007. [PubMed: 17562838] [Full Text: https://doi.org/10.1212/01.wnl.0000264933.56204.e8]
Van Coster, R. N., Gerlo, E. A., Giardina, T. G., Engelke, U. F., Smet, J. E., De Praeter, C. M., Meersschaut, V. A., De Meirleir, L. J., Seneca, S. H., Devreese, B., Leroy, J. G., Herga, S., Perrier, J. P., Wevers, R. A., Lissens, W. Aminoacylase I deficiency: a novel inborn error of metabolism. Biochem. Biophys. Res. Commun. 338: 1322-1326, 2005. [PubMed: 16274666] [Full Text: https://doi.org/10.1016/j.bbrc.2005.10.126]
Voss, R., Lerer, I., Povey, S., Solomon, E., Bobrow, M. Confirmation and further regional assignment of aminoacylase 1 (ACY-1) on human chromosome 3 using a simplified detection method. Ann. Hum. Genet. 44: 1-10, 1980. [PubMed: 6948533] [Full Text: https://doi.org/10.1111/j.1469-1809.1980.tb00940.x]