| *602360 | ||||||||||||||||||
| L-ARGININE:GLYCINE AMIDINOTRANSFERASE; GATM | ||||||||||||||||||
| Alternative titles; symbols | ||||||||||||||||||
| AGAT | ||||||||||||||||||
| HGNC Approved Gene Symbol: GATM | ||||||||||||||||||
| Cytogenetic location: 15q21.1 Genomic coordinates (GRCh37): 15:45,653,321 - 45,670,979 (from NCBI) | ||||||||||||||||||
| Gene Phenotype Relationships | ||||||||||||||||||
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| Cloning | ||||||||||||||||||
| Creatine and phosphocreatine play important roles in the energy metabolism of muscle and nerve tissues. The enzyme L-arginine:glycine amidinotransferase (AGAT; EC 2.1.4.1) catalyzes the transfer of a guanido group from arginine to glycine, forming guanidinoacetic acid, the immediate precursor of creatine. One of the major sites of creatine biosynthesis is the kidney. Humm et al. (1994) isolated and sequenced AGAT from pig kidney mitochondria. Sequence data from the pig AGAT polypeptide allowed them to isolate cDNA clones encoding the human enzyme from a kidney carcinoma cDNA library. The largest human cDNA sequence encodes a 423-amino acid polypeptide including a 37-amino acid signal sequence. The mature porcine and human proteins are 94% identical to each other and 36% identical to bacterial L-arginine:inosamine phosphate amidinotransferase. Humm et al. (1997) noted that mitochondrial and cytosolic forms of AGAT are believed to derive from the same gene by alternative splicing. They expressed human AGAT in E. coli and identified its active-site cysteine residue (cys407). | ||||||||||||||||||
| Gene Structure | ||||||||||||||||||
| Item et al. (2001) stated that the AGAT genomic DNA is 16,858 bp long and consists of 9 exons. | ||||||||||||||||||
| Mapping | ||||||||||||||||||
| Item et al. (2001) stated that the human AGAT gene is located on chromosome 15q15.3 | ||||||||||||||||||
| Molecular Genetics | ||||||||||||||||||
| In 2 sisters with AGAT deficiency (612718) reported by Bianchi et al. (2000), Item et al. (2001) identified a homozygous trp149-to-ter mutation in the GATM gene (W149X; 602360.0001), resulting in undetectable cDNA, as investigated by RT-PCR, as well as in undetectable AGAT activity, as investigated radiochemically in cultivated skin fibroblasts and in virus-transformed lymphoblasts of the patients. The parents were heterozygous for the mutant allele, with intermediate residual AGAT activities. In an affected male cousin of the sibs reported by Bianchi et al. (2000), Battini et al. (2002) identified homozygosity for the same W149X mutation. | ||||||||||||||||||
| Animal Model | ||||||||||||||||||
| Sandell et al. (2003) demonstrated in the mouse that Gatm, which is expressed during development, is imprinted in the placenta and yolk sac, but not in embryonic tissues. The Gatm gene maps to mouse chromosome 2 in a region that had not previously been shown to contain imprinted genes. To determine whether Gatm is located in a cluster of imprinted genes, Sandell et al. (2003) investigated the expression pattern of genes located near Gatm: Duox1 (606758), Duox2 (606759), Slc28a2 (606208), Slc30a4 (602095), and a transcript corresponding to LOC214616 and found no evidence that any is imprinted in placenta. These data were the first to link creatine metabolism with imprinting and the parental 'tug-of-war' for energy resources during development. Although many imprinted genes are associated with differentially methylated CpG islands, the Gatm gene resides in apparent isolation from other imprinted genes and is associated with an unmethylated CpG island. | ||||||||||||||||||
| ALLELIC VARIANTS (Selected Examples): | ||||||||||||||||||
| Table View | ||||||||||||||||||
| .0001 ARGININE:GLYCINE AMIDINOTRANSFERASE DEFICIENCY | ||||||||||||||||||
| GATM, TRP149TER [dbSNP:rs80338737] | ||||||||||||||||||
| In 2 sisters with AGAT deficiency (612718) reported by Bianchi et al. (2000), Item et al. (2001) identified a homozygous 9297G-A transition, converting a tryptophan codon (TGG) to a stop codon (TAG) at residue 149 (W149X) of the GATM gene. In an affected cousin of the sibs reported by Bianchi et al. (2000), Battini et al. (2002) identified homozygosity for the same W149X mutation; his parents and 10 additional subjects in the pedigree were heterozygous for the mutation. | ||||||||||||||||||
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