Alternative titles; symbols
HGNC Approved Gene Symbol: AMPD1
Cytogenetic location: 1p13.2 Genomic coordinates (GRCh38): 1:114,673,098-114,695,546 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1p13.2 | Myopathy due to myoadenylate deaminase deficiency | 615511 | Autosomal recessive | 3 |
The AMPD1 gene encodes myoadenylate deaminase, the skeletal muscle isoform of adenosine monophosphate deaminase (AMPD; EC 3.5.4.6), which catalyzes the deamination of AMP to IMP and plays an important role in the purine nucleotide cycle (summary by Morisaki et al., 1992).
In mammals, AMPD is encoded by a multigene family: AMPD2 (102771) encodes the L (liver) isoform, and AMPD3 (102772) encodes the E (erythrocyte) isoform.
Sabina et al. (1990) cloned and partially sequenced the human and rat muscle-specific genes encoding AMP deaminase. The deduced proteins share 92% sequence homology.
Morisaki et al. (1990) found that AMPD1 is expressed at high levels in skeletal muscle of the adult rat, whereas AMPD2, which they cloned from an adult rat brain cDNA library, is the predominant gene expressed in nonmuscle tissues and smooth muscle of the adult rat and is also the predominant gene expressed in embryonic muscle and undifferentiated myoblasts. Both genes are expressed in cardiac muscle of the adult rat. The peptides encoded by these 2 genes have distinct immunologic properties.
Sabina et al. (1990) determined that the AMPD1 gene is approximately 20 kb long with 16 exons ranging in size from 101 to 220 nucleotides, with the exception of exon 2, which comprises only 12 nucleotides. Intron size ranges from 159 bp for intron 14 to several kilobases.
Morton et al. (1989) used in situ hybridization and somatic cell hybrid analysis to demonstrate that the AMPD1 gene maps to human chromosome 1. By in situ hybridization and analysis of human-mouse somatic cell hybrids, Sabina et al. (1990) localized the AMPD1 gene to 1p21-p13.
Moseley et al. (1990) demonstrated that the mouse Ampd1 gene is located close to Ampd2 on distal chromosome 3.
Morisaki et al. (1990) stated that the conservation of nucleotide sequence and exon/intron boundaries between AMPD1 and AMPD2, as well as their close linkage, suggests that they arose by duplication of a common primordial gene.
In a German woman and 10 other unrelated individuals with myopathy due to myoadenylate deaminase deficiency (MMDD; 615511), Morisaki et al. (1992) identified the same homozygous 34C-T transition in the AMPD1 gene, resulting in a truncated protein (Q12X; 102770.0001). However, this variant was found at high frequency in control populations.
Morisaki et al. (1993) presented a study that provided the possible molecular explanation for the fact that the Q12X mutation so rarely causes significant symptoms. Alternative splicing eliminates exon 2 in 0.6-2% of AMPD1 mRNA transcripts in adult skeletal muscle. Expression studies documented that AMPD1 mRNA, which has exon 2 deleted, encodes a functional AMPD peptide. Variations in splicing patterns may contribute to the variability in clinical symptoms.
Morisaki et al. (2000) reported a Japanese patient with myopathy due apparently to compound heterozygosity for 2 missense mutations in the AMPD1 gene: R388W (102770.0002) in exon 9 and R425H (102770.0003) in exon 10. Prokaryotic expression showed a comparable amount of the AMPD1 peptides but undetectable AMPD activity in the constructs with these mutations.
In 11 unrelated individuals with myopathy due to myoadenylate deaminase deficiency (MMDD; 615511), Morisaki et al. (1992) identified a homozygous 34C-T transition in exon 2 of the AMPD1 gene, resulting in a gln12-to-ter (Q12X) substitution. Skeletal muscle biopsies showed no immunoreactive AMPD1 peptide in these patients, and variable but significantly decreased AMPD1 activity. All individuals also carried a P48L (143C-T) substitution that was shown to have no effect on enzyme activity. The Q12X mutant allele was found in heterozygosity in 17% of Caucasians and 23% of African Americans, whereas none of 106 Japanese subjects surveyed had this mutant allele. The frequency of the mutant allele would account for the 2% reported incidence of AMPD deficiency in muscle biopsies. The restricted distribution and high frequency of this doubly mutated allele suggested that it arose in a remote ancestor of individuals of western European descent.
Castro-Gago et al. (2011) identified a homozygous Q12X mutation in a Spanish infant with hypotonia due to MMDD. She had severe muscle weakness, hypotonia of the trunk and upper limbs, areflexia, and lacked muscle atrophy. Ocular movements were normal; she also had macrocephaly. Skeletal muscle biopsy showed normal levels of all skeletal proteins tested but loss of AMPD1 enzyme activity. Hypotonia persisted, and the child was unable to sit at age 18 months.
In a Japanese woman with adult-onset myopathy due to myoadenylate deaminase deficiency (MMDD; 615511), Morisaki et al. (2000) and Abe et al. (2000) identified compound heterozygous mutations in the AMPD1 gene: arg388-to-trp (R388W) and arg425-to-his (R425H; 102770.0003) in exon 9 and exon 10, respectively. Neither mutation was found in the control population.
For discussion of the arg425-to-his (R425H) mutation in the AMPD1 gene that was found in compound heterozygous state in a patient with adult-onset myopathy due to myoadenylate deaminase deficiency (MMDD; 615511) by Morisaki et al. (2000) and Abe et al. (2000), see 102770.0002.
Abe, M., Higuchi, I., Morisaki, H., Morisaki, T., Osame, M. Myoadenylate deaminase deficiency with progressive muscle weakness and atrophy caused by new missense mutations in AMPD1 gene: case report in a Japanese patient. Neuromusc. Disord. 10: 472-477, 2000. [PubMed: 10996775] [Full Text: https://doi.org/10.1016/s0960-8966(00)00127-9]
Castro-Gago, M., Gomez-Lado, C., Perez-Gay, L., Eiris-Punal, J., Martinez, E. P., Garcia-Consuegra, I., Martin, M. A. Primary adenosine monophosphate (AMP) deaminase deficiency in a hypotonic infant. J. Child Neurol. 26: 734-737, 2011. [PubMed: 21343608] [Full Text: https://doi.org/10.1177/0883073810390367]
Genetta, T., Morisaki, H., Morisaki, T., Holmes, E. W. A novel bipartite intronic splicing enhancer promotes the inclusion of a mini-exon in the AMP deaminase 1 gene. J. Biol. Chem. 276: 25589-25597, 2001. [PubMed: 11331279] [Full Text: https://doi.org/10.1074/jbc.M011637200]
Loh, E., Rebbeck, T. R., Mahoney, P. D., DeNofrio, D., Swain, J. L., Holmes, E. W. Common variant in AMPD1 gene predicts improved clinical outcome in patients with heart failure. Circulation 99: 1422-1425, 1999. [PubMed: 10086964] [Full Text: https://doi.org/10.1161/01.cir.99.11.1422]
Morisaki, H., Higuchi, I., Abe, M., Osame, M., Morisaki, T. First missense mutations (R388W and R425H) of AMPD1 accompanied with myopathy found in a Japanese patient. Hum. Mutat. 16: 467-472, 2000. [PubMed: 11102975] [Full Text: https://doi.org/10.1002/1098-1004(200012)16:6<467::AID-HUMU3>3.0.CO;2-V]
Morisaki, H., Morisaki, T., Newby, L. K., Holmes, E. W. Alternative splicing: a mechanism for phenotypic rescue of a common inherited defect. J. Clin. Invest. 91: 2275-2280, 1993. [PubMed: 8486786] [Full Text: https://doi.org/10.1172/JCI116455]
Morisaki, T., Gross, M., Morisaki, H., Pongratz, D., Zollner, N., Holmes, E. W. Molecular basis of AMP deaminase deficiency in skeletal muscle. Proc. Nat. Acad. Sci. 89: 6457-6461, 1992. [PubMed: 1631143] [Full Text: https://doi.org/10.1073/pnas.89.14.6457]
Morisaki, T., Sabina, R. L., Holmes, E. W. Adenylate deaminase: a multigene family in humans and rats. J. Biol. Chem. 265: 11482-11486, 1990. [PubMed: 2365682] [Full Text: https://linkinghub.elsevier.com/retrieve/pii/S0021-9258(19)38422-4]
Morton, C. C., Eddy, R. L., Shows, T. B., Clark, P. R. H., Sabina, R. L., Holmes, E. W. Human AMP deaminase-1 gene (AMPD1) is mapped to chromosome 1. (Abstract) Cytogenet. Cell Genet. 51: 1048-1049, 1989.
Moseley, W. S., Morisaki, T., Sabina, R. L., Holmes, E. W., Seldin, M. F. Ampd-2 maps to distal mouse chromosome 3 in linkage with Ampd-1. Genomics 6: 572-574, 1990. [PubMed: 2328996] [Full Text: https://doi.org/10.1016/0888-7543(90)90490-l]
Sabina, R. L., Morisaki, T., Clarke, P., Eddy, R., Shows, T. B., Morton, C. C., Holmes, E. W. Characterization of the human and rat myoadenylate deaminase genes. J. Biol. Chem. 265: 9423-9433, 1990. [PubMed: 2345176]
Sabina, R. L., Ogasawara, N., Holmes, E. W. Expression of three stage-specific transcripts of AMP deaminase during myogenesis. Molec. Cell. Biol. 9: 2244-2246, 1989. [PubMed: 2568582] [Full Text: https://doi.org/10.1128/mcb.9.5.2244-2246.1989]