HGNC Approved Gene Symbol: AMACR
SNOMEDCT: 700463002;
Cytogenetic location: 5p13.2 Genomic coordinates (GRCh38): 5:33,986,165-34,008,050 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 5p13.2 | Alpha-methylacyl-CoA racemase deficiency | 614307 | Autosomal recessive | 3 |
| Bile acid synthesis defect, congenital, 4 | 214950 | Autosomal recessive | 3 |
Alpha-methylacyl-CoA racemase (AMACR; EC 5.1.99.4) is a mitochondrial and peroxisomal enzyme that catalyzes the conversion of 2R stereoisomers of phytanic and pristanic acid to their S counterparts. AMACR is essential for beta oxidation of branched-chain fatty acids and bile acid intermediates, such as dihydroxycholestanoic acid and trihydroxycholestanoic acid (summary by Mubiru et al., 2004).
By Western blot analysis of rat and human liver, Schmitz et al. (1995) found that AMACR had an apparent molecular mass of 47 kD. Amacr activity comigrated with a mitochondrial marker in fractionation of rat liver. In contrast, human AMACR comigrated with markers of both mitochondria and peroxisomes in fractionated fibroblasts and HepG2 cells.
By EST database searching, Ferdinandusse et al. (2000) identified a human AMACR cDNA. The deduced 382-amino acid protein shares 81% and 77% sequence identity with the rat and mouse homologs, respectively.
Using the rat sequence to query an EST database, followed by 5-prime RACE of a liver cDNA library, Amery et al. (2000) cloned human AMACR. The deduced 382-amino acid protein has a functional N-terminal mitochondrial targeting signal, a putative mitochondrial matrix processing motif, and a C-terminal peroxisomal targeting signal. EST database analysis revealed AMACR expression in most human tissues. Western blot analysis detected AMACR at an apparent molecular mass of 42 kD. Western blot analysis of rat tissues detected a clear signal only in liver and kidney.
Mubiru et al. (2004) identified 5 alternative splice variants of AMACR in normal prostate and prostate tumor tissues. The transcripts differ in inclusion or exclusion of exon 3, use of alternative exon 5, and alternative splicing within the alternative exon 5. Exclusion of exon 3 results in a frameshift. The deduced proteins have calculated molecular masses of 22.2 to 42.4 kD and differ only at their C termini. Only full-length AMACR contains a C-terminal peroxisomal targeting site. Another isoform has a C-terminal sequence similar to a sequence in mitochondrial fumarate hydratase (FH; 136850). All 5 isoforms have the N-terminal mitochondrial targeting sequence. Immunohistochemical analysis of normal and tumor prostate tissue revealed isoform-specific staining patterns.
Mubiru et al. (2004) determined that the AMACR gene contains 6 exons, including an alternative exon 5.
By sequence analysis, Ferdinandusse et al. (2000) mapped the AMACR gene to chromosome 5p13.2-q11.1. By genomic sequence analysis, Amery et al. (2000) mapped the AMACR gene to chromosome 5p13-p11.
Schmitz et al. (1995) characterized purified human liver AMACR and found that it had a pH optimum between pH 7 and 8 and functioned as a monomer. AMACR acted only on coenzyme A thioesters, not on free fatty acids, and accepted as substrates a wide range of alpha-methylacyl-CoAs, including pristanoyl-CoA and trihydroxycoprostanoyl-CoA, an intermediate in bile acid synthesis. It did not accept 3-methyl-branched or linear chain acyl-CoAs.
AMACR Deficiency
Ferdinandusse et al. (2000) described 2 patients with an adult-onset neurologic disorder associated with elevated plasma concentrations of pristanic acid (a branched-chain fatty acid) and C27 bile acid intermediates (614307). One patient also had pigmentary retinopathy, suggesting Refsum disease (266500), whereas the other patient had upper motor neuron signs in the legs, suggesting adrenomyeloneuropathy (300100). Sequence analysis of AMACR cDNA from the patients identified a homozygous mutation (S52P; 604489.0001) in both patients. In vitro functional expression studies showed an absence of enzyme activity.
Congenital Bile Acid Synthesis Defect 4
In a child with a defect in bile acid synthesis (CBAS4; 214950), Ferdinandusse et al. (2000) identified a homozygous mutation in the AMACR gene (604489.0002).
In an infant with a defect in bile acid synthesis, Setchell et al. (2003) identified a homozygous mutation in the AMACR gene (S52P; 604489.0001).
Savolainen et al. (2004) generated a knockout mouse model of AMACR deficiency. Despite a 44-fold accumulation of C27 bile acid precursors and decreased (less than 50%) primary (C24) bile acids in bile, serum, and liver, the Amacr -/- mice were clinically symptomless. Real-time quantitative PCR analysis showed that, among other responses, the level of mRNA for peroxisomal multifunctional enzyme-1 (pMFE1; see 601860) was increased 3-fold in Amacr -/- mice. Together with CYP3A11 (CYP3A4; 124010) and CYP46A1 (604087), pMFE1 participates in an Amacr-independent pathway for the generation of C24 bile acids. Exposure of Amacr -/- mice to a diet supplemented with phytol, a source for branched-chain fatty acids, triggered the development of a disease state with liver manifestations. The authors proposed elimination of phytol from the diet of patients suffering from Amacr deficiency.
AMACR Deficiency
Ferdinandusse et al. (2000) found a missense mutation in AMACR, ser52-to-pro (S52P), in 2 adult patients with adult-onset sensorimotor neuropathy and deficiency of alpha-methylacyl-CoA racemase (614307). Both of these patients had 2 missense polymorphisms (V9M and G175D) in addition to S52P. Patient-derived fibroblasts showed complete absence of AMACR activity.
Clarke et al. (2004), Thompson et al. (2008), and Smith et al. (2010) identified a homozygous S52P mutation in unrelated patients with adult-onset AMACR deficiency.
Dick et al. (2011) reported homozygosity for the S52P mutation in a 58-year-old man who presented with an 8-year history of gait unsteadiness, cerebellar dysarthria, a few tonic/clonic seizures, and decline in short-term memory. Nerve conduction studies showed a mild sensorimotor polyneuropathy, and brain MRI showed high signal on T2-weighted images in the white matter of the cerebral hemispheres, thalami, midbrain, and pons, with brainstem atrophy. There was also some frontal atrophy. Laboratory studies showed increased phytanic and pristanic acids, indicating a peroxisomal disorder. Dick et al. (2011) noted the unusual phenotypic presentation in this patient, with minimal cognitive decline and prominent cerebellar ataxia.
Bile Acid Synthesis Defect, Congenital, 4
Setchell et al. (2003) reported an infant with a defect in bile acid synthesis (CBAS4; 214950) who was homozygous for the S52P mutation, resulting from a 154T-C transition in exon 1 of the AMACR gene. The patient presented in the first months of life with fat-soluble vitamin deficiencies, coagulopathy, and cholestatic liver disease. Analysis of bile acids in urine, serum, and bile showed high concentrations of 3-alpha-7-alpha-12-alpha-trihydroxy-5-beta-cholestanoic acid (THCA) similar to that seen in Zellweger syndrome (see 214100) and in the American alligator (Alligator mississippiensis). A earlier-born affected sib, who died at age 6 months, also had the mutation.
In a child with a defect in bile acid synthesis (CBAS4; 214950), Ferdinandusse et al. (2000) identified a homozygous 320T-C transition in the AMACR gene, resulting in a leu107-to-pro (L107P) substitution. Functional expression studies of the mutation in E. coli showed complete absence of enzyme activity. The child had previously been reported by Sequeira et al. (1998) as having Niemann-Pick disease type C (257220) in addition to defective peroxisomal beta-oxidation. Steatorrhea and fat-soluble vitamin malabsorption responded well to bile acid therapy.
Amery, L., Fransen, M., De Nys, K., Mannaerts, G. P., Van Veldhoven, P. P. Mitochondrial and peroxisomal targeting of 2-methylacyl-CoA racemase in humans. J. Lipid Res. 41: 1752-1759, 2000. [PubMed: 11060344]
Clarke, C. E., Alger, S., Preece, M. A., Burdon, M. A., Chavda, S., Denis, S., Ferdinandusse, S., Wanders, R. J. A. Tremor and deep white matter changes in alpha-methylacyl-CoA racemase deficiency. Neurology 63: 188-189, 2004. [PubMed: 15249642] [Full Text: https://doi.org/10.1212/01.wnl.0000132841.81250.b7]
Dick, D., Horvath, R., Chinnery, P. F. AMACR mutations cause late-onset autosomal recessive cerebellar ataxia. Neurology 76: 1768-1770, 2011. [PubMed: 21576695] [Full Text: https://doi.org/10.1212/WNL.0b013e31821a4484]
Ferdinandusse, S., Denis, S., Clayton, P. T., Graham, A., Rees, J. E., Allen, J. T., McLean, B. N., Brown, A. Y., Vreken, P., Waterham, H. R., Wanders, R. J. A. Mutations in the gene encoding peroxisomal alpha-methylacyl-CoA racemase cause adult-onset sensory motor neuropathy. Nature Genet. 24: 188-191, 2000. [PubMed: 10655068] [Full Text: https://doi.org/10.1038/72861]
Mubiru, J. N., Shen-Ong, G. L., Valente, A. J., Troyer, D. A. Alternative spliced variants of the alpha-methylacyl-CoA racemase gene and their expression in prostate cancer. Gene 327: 89-98, 2004. [PubMed: 14960364] [Full Text: https://doi.org/10.1016/j.gene.2003.11.009]
Savolainen, S., Kotti, T. J., Schmitz, W., Savolainen, T. I., Sormunen, R. T., Ilves, M., Vainio, S. J., Conzelmann, E., Hiltunen, J. K. A mouse model for alpha-methylacyl-CoA racemase deficiency: adjustment of bile acid synthesis and intolerance to dietary methyl-branched lipids. Hum. Molec. Genet. 13: 955-965, 2004. [PubMed: 15016763] [Full Text: https://doi.org/10.1093/hmg/ddh107]
Schmitz, W., Albers, C., Fingerhut, R., Conzelmann, E. Purification and characterization of an alpha-methylacyl-CoA racemase from human liver. Europ. J. Biochem. 231: 815-822, 1995. [PubMed: 7649182] [Full Text: https://doi.org/10.1111/j.1432-1033.1995.tb20766.x]
Sequeira, J. S. S., Vellodi, A., Vanier, M. T., Clayton, P. T. Niemann-Pick disease type C and defective peroxisomal beta-oxidation of branched-chain substrates. J. Inherit. Metab. Dis. 21: 149-154, 1998. [PubMed: 9584266] [Full Text: https://doi.org/10.1023/a:1005395709826]
Setchell, K. D. R., Heubi, J. E., Bove, K. E., O'Connell, N. C., Brewsaugh, T., Steinberg, S. J., Moser, A., Squires, R. H., Jr. Liver disease caused by failure to racemize trihydroxycholestanoic acid: gene mutation and effect of bile acid therapy. Gastroenterology 124: 217-232, 2003. [PubMed: 12512044] [Full Text: https://doi.org/10.1053/gast.2003.50017]
Smith, E. H., Gavrilov, D. K., Oglesbee, D., Freeman, W. D., Vavra, M. W., Matern, D., Tortorelli, S. An adult onset case of alpha-methyl-acyl-CoA racemase deficiency. J. Inherit. Metab. Dis. 33 (suppl. 3): S349-S353, 2010. [PubMed: 20821052] [Full Text: https://doi.org/10.1007/s10545-010-9183-6]
Thompson, S. A., Calvin, J., Hogg, S., Ferdinandusse, S., Wanders, R. J. A., Barker, R. A. Relapsing encephalopathy in a patient with alpha-methylacyl-CoA racemase deficiency. J. Neurol. Neurosurg. Psychiat. 79: 448-450, 2008. [PubMed: 18032455] [Full Text: https://doi.org/10.1136/jnnp.2007.129478]