HGNC Approved Gene Symbol: AMPD2
SNOMEDCT: 726610000;
Cytogenetic location: 1p13.3 Genomic coordinates (GRCh38): 1:109,619,837-109,632,055 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1p13.3 | ?Spastic paraplegia 63, autosomal recessive | 615686 | Autosomal recessive | 3 |
| Pontocerebellar hypoplasia, type 9 | 615809 | Autosomal recessive | 3 |
The AMPD2 gene encodes adenosine monophosphate deaminase-2 (EC 3.5.4.6), an enzyme that catalyzes the deamination of AMP to IMP and plays an important role in the purine nucleotide cycle (summary by Akizu et al., 2013).
By screening a human spleen cDNA library with a previously cloned partial rat AMPD2 cDNA, followed by the use of PCR techniques, Bausch-Jurken et al. (1992) isolated cDNA clones for human AMPD2 from T-lymphoblast and placenta libraries. The deduced 760-amino acid polypeptide has a predicted molecular mass of 88.1 kD and shares significant homology in the C-terminal region with AMPD1 (102770). AMPD2 encodes isoform L (liver).
Morisaki et al. (1990) found that whereas AMPD1 is expressed at high levels in skeletal muscle of the adult rat, 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. Human isoform L corresponds to rat isoform B (liver and kidney).
Akizu et al. (2013) found high expression of AMPD2 in human cerebellum.
By Southern blot analysis, Moseley et al. (1990) demonstrated that distinct restriction fragments in the rat and human genome hybridized to AMPD1 and AMPD2 cDNAs. Indirect evidence suggested that the 2 genes are linked; L6 myoblasts resistant to coformycin coamplified both genes while expressing only AMPD2. Moseley et al. (1990) demonstrated further that Ampd1 and Ampd2 are closely linked on distal mouse chromosome 3.
By studies of human/mouse somatic cell hybrids, Eddy et al. (1993) demonstrated that the AMPD2 gene is localized to 1p, as is AMPD1.
Mahnke-Zizelman et al. (1996) refined the map location of AMPD2 to chromosome 1p13.3 using somatic cell hybrids and fluorescence in situ hybridization.
Mahnke-Zizelman et al. (1996) showed that the AMPD2 gene contains 19 exons and spans 14 kb of genomic DNA. Alternatively spliced forms arise from the use of either exon 1A or exon 1B, both of which have promoter activity and contain an initiation codon.
Van den Berghe and Hers (1980) noted that AMP deaminase is normally about 95% inhibited by guanosine triphosphate (GTP) and may be the limiting step in adenine nucleotide catabolism. They studied the liver from a man with familial primary gout and found defective inhibition of AMP deaminase by GTP. The authors suggested that a genetically determined reduction in sensitivity of AMP deaminase to inhibition might be a basis for primary gout.
Spastic Paraplegia 63, Autosomal Recessive
In affected members of a consanguineous family segregating spastic paraplegia-63 (SPG63; 615686), Novarino et al. (2014) identified a homozygous frameshift mutation in the AMPD2 gene (102771.0001).
Pontocerebellar Hypoplasia Type 9
In 8 patients from 5 families with pontocerebellar hypoplasia type 9 (PCH9; 615809), Akizu et al. (2013) identified 5 different homozygous mutations in the AMPD2 gene (102771.0002-102771.0006). Two mutations resulted in premature termination, whereas 3 were missense mutations at highly conserved residues. The mutations were found by whole-exome sequencing of 30 probands with PCH. The AMPD2 protein was nearly completely absent in patient cells, and the mutations failed to rescue growth defects in knockdown studies of the yeast homolog Amd1. The findings were consistent with null alleles, although 2 missense mutations showed some residual AMP deaminase activity in conditions of overexpression. The patients had microcephaly (up to -9 SD), profoundly delayed psychomotor development, and spasticity. All except 2 had seizures. Brain imaging showed pontocerebellar hypoplasia with a 'figure 8' appearance of the brainstem, as well as cerebral cortical atrophy and corpus callosum hypoplasia. Studies in patient cells showed a dose-dependent negative effect of adenosine on cell survival and decreased protein translation following adenosine treatment. Patient cells had increased levels of ATP and decreased levels of guanine nucleotides, which suggested a blockage of de novo purine biosynthesis in proliferating neural progenitor cells. The findings suggested that AMPD2 plays a role in the maintenance of cellular guanine nucleotide pools by regulating the feedback inhibition of adenosine derivatives on de novo purine synthesis through IMP. In turn, decreased levels of guanine result in defective GTP-dependent initiation of protein translation. These defects could be rescued in vitro by administration of ribonucleotide purine precursors.
In 4 sibs, born of consanguineous parents of Middle Eastern descent, with PCH9, Marsh et al. (2015) identified a homozygous truncating mutation in the AMPD2 gene (Y752X; 102771.0007). The mutation, which was found by a combination of linkage analysis and whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Western blot analysis of patient cells showed complete absence of the AMPD2 protein. Functional studies of the variant were not performed. Two of the patients developed axonal neuropathy in the second decade.
Akizu et al. (2013) found that Ampd2-null mice had normal brain histology. Mice with double knockout of Ampd2 and Ampd3 (102772) had a slightly reduced brain and body weight compared to wildtype, but there was little evidence of neuronal loss early in life. However, they had a severely shortened life span limited to 2 or 3 weeks. After P14, they developed a neurodegenerative phenotype and abnormal gait. Brain studies showed degeneration of the CA3 pyramidal neurons in the hippocampus as well as sparse pyknotic cells in the cortex and cerebellum. These changes were associated with a 25% increase in ATP nucleotide levels and a 33% decrease in GTP levels compared to wildtype.
In 2 affected cousins in a highly consanguineous family (family 1526) segregating spastic paraplegia (SPG63; 615686), Novarino et al. (2014) identified a 1-bp deletion (318delT) in the AMPD2 gene, resulting in a frameshift and premature termination (Cys107Alafs365Ter). This homozygous mutation was found only in affected individuals of the family.
In a Turkish girl with pontocerebellar hypoplasia type 9 (PCH9; 615809), Akizu et al. (2013) identified a homozygous 1-bp deletion (c.1652delG) in exon 12 of the AMPD2 gene, resulting in a frameshift and premature termination (Asp552ThrfsTer66). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not present in publicly available SNP databases or in 1,500 in-house exomes.
In 2 Egyptian sisters with pontocerebellar hypoplasia type 9 (PCH9; 615809), Akizu et al. (2013) identified a homozygous c.2332G-C transversion in exon 17 of the AMPD2 gene, resulting in a glu778-to-asp (E778D) substitution at a highly conserved residue in an alpha-helix domain important for protein structure. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not present in publicly available SNP databases or in 1,500 in-house exomes.
In 2 Saudi brothers with pontocerebellar hypoplasia type 9 (PCH9; 615809), Akizu et al. (2013) identified a homozygous c.1047C-A transversion in exon 8 of the AMPD2 gene, resulting in a tyr349-to-ter (Y349X) substitution. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not present in publicly available SNP databases or in 1,500 in-house exomes.
In an Egyptian boy with pontocerebellar hypoplasia type 9 (PCH9; 615809), Akizu et al. (2013) identified a homozygous c.2377G-T transversion in exon 17 of the AMPD2 gene, resulting in an asp793-to-tyr (D793Y) substitution at a highly conserved residue in an alpha-helix domain important for protein structure. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not present in publicly available SNP databases or in 1,500 in-house exomes.
In 2 Saudi brothers with pontocerebellar hypoplasia type 9 (PCH9; 615809), Akizu et al. (2013) identified a homozygous c.2021G-A transition in exon 14 of the AMPD2 gene, resulting in an arg674-to-his (R674H) substitution at a highly conserved residue in an alpha-helix domain important for protein structure. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not present in publicly available SNP databases or in 1,500 in-house exomes.
In 4 sibs, born of consanguineous Middle Eastern parents, with pontocerebellar hypoplasia type 9 (PCH9; 615809), Marsh et al. (2015) identified a homozygous c.2256C-G transversion (c.2256C-G, NM_001257360.1) in the AMPD2 gene, resulting in a tyr752-to-ter (Y752X) substitution. The mutation, which as found by a combination of linkage analysis and whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Western blot analysis of patient cells showed complete absence of the AMPD2 protein. Functional studies of the variant were not performed. Two of the patients developed axonal neuropathy in the second decade.
Akizu, N., Cantagrel, V., Schroth, J., Cai, N., Vaux, K., McCloskey, D., Naviaux, R. K., Van Vleet, J., Fenstermaker, A. G., Silhavy, J. L., Scheliga, J. S., Toyama, K., and 16 others. AMPD2 regulates GTP synthesis and is mutated in a potentially treatable neurodegenerative brainstem disorder. Cell 154: 505-517, 2013. [PubMed: 23911318] [Full Text: https://doi.org/10.1016/j.cell.2013.07.005]
Bausch-Jurken, M. T., Mahnke-Zizelman, D. K., Morisaki, T., Sabina, R. L. Molecular cloning of AMP deaminase isoform L. J. Biol. Chem. 267: 22407-22413, 1992. [PubMed: 1429593]
Eddy, R. L., Mahnke-Zizelman, D. K., Bausch-Jurken, M. T., Sabina, R. L., Shows, T. B. Distribution of the AMP deaminase multigene family within the human genome: assignment of the AMPD2 to chromosome 1p21-p34 and AMPD3 to chromosome 11p13-pter. (Abstract) Human Genome Mapping Workshop 93, Kobe, Japan 1993. P. 24.
Mahnke-Zizelman, D. K., Van den Bergh, F., Bausch-Jurken, M. T., Eddy, R., Sait, S., Shows, T. B., Sabina, R. L. Cloning, sequence and characterization of the human AMPD2 gene: evidence for transcriptional regulation by two closely spaced promoters. Biochim. Biophys. Acta 1308: 122-132, 1996. [PubMed: 8764830] [Full Text: https://doi.org/10.1016/0167-4781(96)00089-9]
Marsh, A. P. L., Lukic, V., Pope, K., Bromhead, C., Tankard, R., Ryan, M. M., Yiu, E. M., Sim, J. C. H., Delatycki, M. B., Amor, D. J., McGillivray, G., Sherr, E. H., Bahlo, M., Leventer, R. J., Lockhart, P. J. Complete callosal agenesis, pontocerebellar hypoplasia, and axonal neuropathy due to AMPD2 loss. Neurol. Genet. 1: e16, 2015. Note: Electronic Article. [PubMed: 27066553] [Full Text: https://doi.org/10.1212/NXG.0000000000000014]
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]
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]
Novarino, G., Fenstermaker, A. G., Zaki, M. S., Hofree, M., Silhavy, J. L., Heiberg, A. D., Abdellateef, M., Rosti, B., Scott, E., Mansour, L., Masri, A., Kayserili, H., and 41 others. Exome sequencing links corticospinal motor neuron disease to common neurodegenerative disorders. Science 343: 506-511, 2014. [PubMed: 24482476] [Full Text: https://doi.org/10.1126/science.1247363]
Van den Berghe, G., Hers, H. G. Abnormal AMP deaminase in primary gout. (Letter) Lancet 316: 1090 only, 1980. Note: Originally Volume II. [PubMed: 6107718] [Full Text: https://doi.org/10.1016/s0140-6736(80)92320-x]