Alternative titles; symbols
HGNC Approved Gene Symbol: GATM
SNOMEDCT: 702440000;
Cytogenetic location: 15q21.1 Genomic coordinates (GRCh38): 15:45,361,124-45,402,227 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 15q21.1 | Cerebral creatine deficiency syndrome 3 | 612718 | Autosomal recessive | 3 |
| Fanconi renotubular syndrome 1 | 134600 | Autosomal dominant | 3 |
Creatine and phosphocreatine play important roles in the energy metabolism of muscle and nerve tissues. The enzyme L-arginine:glycine amidinotransferase (GATM; EC 2.1.4.1) catalyzes the transfer of a guanido group from arginine to glycine, forming guanidinoacetic acid, the immediate precursor of creatine. The major sites of creatine biosynthesis are pancreas, kidney, and liver, where GATM appears to be located in mitochondria of cells (summary by Humm et al., 1994).
Humm et al. (1994) isolated and sequenced Gatm, which they called 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).
Item et al. (2001) stated that the GATM genomic DNA is 16,858 bp long and contains 9 exons.
Item et al. (2001) stated that the human GATM gene is located on chromosome 15q15.3.
Gross (2016) mapped the GATM gene to chromosome 15q21.1 based on an alignment of the GATM sequence (GenBank BC004141) with the genomic sequence (GRCh38).
Cerebral Creatine Deficiency Syndrome 3
In 2 sisters with cerebral creatine deficiency syndrome-3 (CCDS3; 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.
In 2 sibs, born of unrelated Yemenite Jewish parents, with cerebral creatine deficiency syndrome-3, Edvardson et al. (2010) identified a homozygous truncating mutation in the GATM gene (602360.0002).
Fanconi Renotubular Syndrome 1
In 28 affected members from 5 unrelated families with Fanconi renotubular syndrome-1 (FRTS1; 134600), Reichold et al. (2018) identified 4 different heterozygous missense mutations in the GATM gene (P320S, 602360.0006; T336A, 602360.0007; T336I, 602360.0008; and P34L, 602360.0009). The mutations, which were found by a combination of linkage analysis and candidate gene sequencing, next-generation gene sequencing, and exome sequencing, were confirmed by Sanger sequencing; the variants segregated with the disorder in all families. In silico modeling suggested that the mutations may adversely affect protein folding and possibly predispose the mutant protein to aggregation. Overexpression of the mutations in renal proximal tubule cells resulted in abnormal and elongated mitochondria containing GATM-positive fibrillary aggregates, similar to the deposits observed in the proximal tubules of patient renal biopsies. Cells transfected with the T336A mutation showed decreased mitochondrial turnover rate, increased reactive oxygen species (ROS), activation of the inflammasome, including elevated IL18 (600953), increased levels of fibronectin and actin mRNA, and increased cell death compared to controls. These findings provided a mechanistic link between kidney fibrosis and progressive renal failure observed in the patients. Examination of Gatm-null mice showed no evidence of aminoaciduria or glycosuria, consistent with no effect on renal proximal tubular function. However, treatment of rats with oral creatine reduced renal Gatm expression and protein levels, suggesting that it could be a possible intervention to suppress the endogenous production of mutant GATM and dampen the formation of deleterious mitochondrial deposits.
Associations Pending Confirmation
Mangravite et al. (2013) identified a downstream target of statin treatment by screening for the effects of in vitro statin exposure on genetic associations with gene expression levels in lymphoblastoid cell lines derived from 480 participants of a clinical trial of simvastatin treatment. This analysis identified 6 expression quantitative trait loci (eQTLs) that interacted with simvastatin exposure, including rs9806699, a cis-eQTL for the GATM gene, which encodes the rate-limiting enzyme in creatine synthesis. Mangravite et al. (2013) found this locus to be associated with incidence of statin-induced myotoxicity in 2 separate populations (metaanalysis odds ratio = 0.60). Furthermore, Mangravite et al. (2013) found that GATM knockdown in hepatocyte-derived cell lines attenuated transcriptional response to sterol depletion, demonstrating that GATM may act as a functional link between statin-mediated lowering of cholesterol and susceptibility to statin-induced myopathy.
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.
Choe et al. (2013) found that Gatm -/- mice were born at the expected mendelian ratio. Gatm -/- mice did not require special treatment for survival, but they showed multiple abnormalities, and both sexes were infertile. Gatm -/- mice were lean and short with markedly reduced body mass index, accompanied by low serum leptin (LEP; 164160) levels and the expected creatine deficiency. Gatm -/- mice showed increased food intake compared with controls. They also showed reduced locomotor activity, reduced body tension, and severe scoliosis, indicating chronic muscular hypotonia. Creatine deficiency in Gatm -/- mice resulted in chronic Ampk (see 602739) activation in skeletal muscle, white adipose tissue, liver, and hypothalamus, concomitant with reduced muscular nucleoside triphosphate content and inhibition of acetyl-CoA carboxylase (see 200350) in muscle, adipose, and liver. Conversely, creatine deficiency improved glucose tolerance in Gatm -/- mice and protected them from metabolic syndrome induced by a high-fat diet. Oral creatine administration largely reversed the phenotype of Gatm -/- mice.
In 2 sisters with cerebral creatine deficiency syndrome-3 (CCDS3; 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.
In 2 sibs, born of unrelated Yemenite Jewish parents, with cerebral creatine deficiency syndrome-3 (CCDS3; 612718), Edvardson et al. (2010) identified a homozygous 1-bp insertion (1111insA) in the GATM gene, resulting in a frameshift and premature termination at codon 376. Each unaffected parent was heterozygous for the mutation, which was not found in 57 ethnic controls. Both patients showed delayed psychomotor development in infancy with poor speech acquisition. Each also had symptoms of a myopathy, with easy fatigability and predominantly proximal muscle weakness and atrophy. Brain MRS showed decreased creatine, and urine guanidinoacetate levels were low. Treatment with oral creatine resulted in clinical improvement and increased cerebral creatine levels.
In 2 Jordanian sibs, born of consanguineous parents, with cerebral creatine deficiency syndrome 3 (CCDS3; 612718), Verma (2010) identified a homozygous arg169-to-ter (R169X) substitution in the GATM gene. Both patients showed delayed development in early childhood and began to show progressive proximal muscle weakness with features of a myopathy in their late teens. Laboratory studies showed undetectable GAA levels. Treatment with oral creatine supplementation resulted in dramatic improvement of muscle strength, but speech and cognitive impairment were unchanged.
Comeaux et al. (2013) reported 2 sibs with CCDSD3 who were homozygous for a c.505C-T transition in exon 4 of the GATM gene, resulting in an R169X substitution.
In a Chinese girl with cerebral creatine deficiency syndrome-3 (CCDS3; 612718), Ndika et al. (2012) identified a homozygous G-to-T transversion in intron 3 of the GATM gene (c.484+1G-T), resulting in a splice site and a truncated protein lacking exon 3 (Ala97ValfsTer11). The mutant transcript was subject to nonsense-mediated mRNA decay. Each unaffected parent was heterozygous for the mutation. GATM activity was not detectable in patient cells. The patient showed significant developmental progress after early and intense treatment with creatine supplementation.
In 2 sisters, born of consanguineous parents, with cerebral creatine deficiency syndrome-3 (CCDS3; 612718), Nouioua et al. (2013) identified a homozygous c.608A-C transversion in exon 4 of the GATM gene, resulting in a tyr203-to-ser (Y203S) substitution at a highly conserved residue. Each unaffected parent was heterozygous for the mutation, which was not found in 210 control alleles.
In affected members of a family with Fanconi renotubular syndrome-1 (FRTS1; 134600), Reichold et al. (2018) identified a heterozygous c.958C-T transition (c.958C-T, NM_001482.1) in the GATM gene, resulting in a pro320-to-ser (P320S) substitution at a highly conserved residue. Overexpression of the mutation in a renal proximal tubule cell resulted in abnormal and elongated mitochondria containing GATM-positive fibrillary aggregates, similar to the deposits observed in the proximal tubules of patient renal biopsies.
In affected members of a family with Fanconi renotubular syndrome-1 (FRTS1; 134600), Reichold et al. (2018) identified a heterozygous c.1006A-G transition (c.1006A-G, NM_001482.1) in the GATM gene, resulting in a thr336-to-ala (T336A) substitution at a highly conserved residue. Overexpression of the mutation in a renal proximal tubule cell resulted in abnormal and elongated mitochondria containing GATM-positive fibrillary aggregates, similar to the deposits observed in the proximal tubules of patient renal biopsies.
In affected members of a family with Fanconi renotubular syndrome-1 (FRTS1; 134600), Reichold et al. (2018) identified a heterozygous c.1007C-T transition (c.1007C-T, NM_001482.1) in the GATM gene, resulting in a thr336-to-ile (T336I) substitution at a highly conserved residue. Overexpression of the mutation in a renal proximal tubule cell resulted in abnormal and elongated mitochondria containing GATM-positive fibrillary aggregates, similar to the deposits observed in the proximal tubules of patient renal biopsies.
In affected members of a family with Fanconi renotubular syndrome-1 (FRTS1; 134600), Reichold et al. (2018) identified a heterozygous c.1022C-T transition (c.1022C-T, NM_001482.1) in the GATM gene, resulting in a pro341-to-leu (P341L) substitution at a highly conserved residue. Overexpression of the mutation in a renal proximal tubule cell resulted in abnormal and elongated mitochondria containing GATM-positive fibrillary aggregates, similar to the deposits observed in the proximal tubules of patient renal biopsies.
Battini, R., Leuzzi, V., Carducci, C., Tosetti, M., Bianchi, M. C., Item, C. B., Stockler-Ipsiroglu, S., Cioni, G. Creatine depletion in a new case with AGAT deficiency: clinical and genetic study in a large pedigree. Molec. Genet. Metab. 77: 326-331, 2002. [PubMed: 12468279] [Full Text: https://doi.org/10.1016/s1096-7192(02)00175-0]
Bianchi, M. C., Tosetti, M., Fornai, F., Alessandri, M. G., Cipriani, P., De Vito, G., Canapicchi, R. Reversible brain creatine deficiency in two sisters with normal blood creatine level. Ann. Neurol. 47: 511-513, 2000. [PubMed: 10762163]
Choe, C., Nabuurs, C., Stockebrand, M. C., Neu, A., Nunes, P., Morellini, F., Sauter, K., Schillemeit, S., Hermans-Borgmeyer, I., Marescau, B., Heerschap, A., Isbrandt, D. L-arginine:glycine amidinotransferase deficiency protects from metabolic syndrome. Hum. Molec. Genet. 22: 110-123, 2013. Note: Erratum: Hum. Molec. Genet.: 22: 4030 only, 2013. [PubMed: 23026748] [Full Text: https://doi.org/10.1093/hmg/dds407]
Comeaux, M. S., Wang, J., Wang, G., Kleppe, S., Zhang, V. W., Schmitt, E. S., Craigen, W. J., Renaud, D., Sun, Q., Wong, L.-J. Biochemical, molecular, and clinical diagnoses of patients with cerebral creatine deficiency syndromes. Molec. Genet. Metab. 109: 260-268, 2013. [PubMed: 23660394] [Full Text: https://doi.org/10.1016/j.ymgme.2013.04.006]
Edvardson, S., Korman, S. H., Livne, A., Shaag, A., Saada, A., Nalbandian, R., Allouche-Arnon, H., Gomori, J. M., Katz-Brull, R. L-arginine:glycine amidinotransferase (AGAT) deficiency: clinical presentation and response to treatment in two patients with a novel mutation. Molec. Genet. Metab. 101: 228-232, 2010. [PubMed: 20682460] [Full Text: https://doi.org/10.1016/j.ymgme.2010.06.021]
Gross, M. B. Personal Communication. Baltimore, Md. 4/14/2016.
Humm, A., Fritsche, E., Mann, K., Gohl, M., Huber, R. Recombinant expression and isolation of human L-arginine:glycine amidinotransferase and identification of its active-site cysteine residue. Biochem. J. 322: 771-776, 1997. [PubMed: 9148748] [Full Text: https://doi.org/10.1042/bj3220771]
Humm, A., Huber, R., Mann, K. The amino acid sequences of human and pig L-arginine:glycine amidinotransferase. FEBS Lett. 339: 101-107, 1994. [PubMed: 8313955] [Full Text: https://doi.org/10.1016/0014-5793(94)80394-3]
Item, C. B., Stockler-Ipsiroglu, S., Stromberger, C., Muhl, A., Alessandri, M. G., Bianchi, M. C., Tosetti, M., Fornai, F., Cioni, G. Arginine:glycine amidinotransferase deficiency: the third inborn error of creatine metabolism in humans. Am. J. Hum. Genet. 69: 1127-1133, 2001. [PubMed: 11555793] [Full Text: https://doi.org/10.1086/323765]
Mangravite, L. M., Engelhardt, B. E., Medina, M. W., Smith, J. D., Brown, C. D., Chasman, D. I., Mecham, B. H., Howie, B., Shim, H., Naidoo, D., Feng, Q., Rieder, M. J., and 11 others. A statin-dependent QTL for GATM expression is associated with statin-induced myopathy. Nature 502: 377-380, 2013. [PubMed: 23995691] [Full Text: https://doi.org/10.1038/nature12508]
Ndika, J. D. T., Johnston, K., Barkovich, J. A., Wirt, M. D., O'Neill, P., Betsalel, O. T., Jakobs, C., Salomons, G. S. Developmental progress and creatine restoration upon long-term creatine supplementation of a patient with arginine:glycine amidinotransferase deficiency. Molec. Genet. Metab. 106: 48-54, 2012. [PubMed: 22386973] [Full Text: https://doi.org/10.1016/j.ymgme.2012.01.017]
Nouioua, S., Cheillan, D., Zaouidi, S., Salomons, G. S., Amedjout, N., Kessaci, F., Boulahdour, N., Hamadouche, T., Tazir, M. Creatine deficiency syndrome: a treatable myopathy due to arginine-glycine amidinotransferase (AGAT) deficiency. Neuromusc. Disord. 23: 670-674, 2013. [PubMed: 23770102] [Full Text: https://doi.org/10.1016/j.nmd.2013.04.011]
Reichold, M., Klootwijk, E. D., Reinders, J., Otto, E. A., Milani, M., Broeker, C., Laing, C., Wiesner, J., Devi, S., Zhou, W., Schmitt, R., Tegtmeier, I., and 42 others. Glycine amidinotransferase (GATM), renal Fanconi syndrome, and kidney failure. J. Am. Soc. Nephrol. 29: 1849-1858, 2018. [PubMed: 29654216] [Full Text: https://doi.org/10.1681/ASN.2017111179]
Sandell, L. L., Guan, X.-J., Ingram, R., Tilghman, S. M. Gatm, a creatine synthesis enzyme, is imprinted in mouse placenta. Proc. Nat. Acad. Sci. 100: 4622-4627, 2003. [PubMed: 12671064] [Full Text: https://doi.org/10.1073/pnas.0230424100]
Verma, A. Arginine:glycine amidinotransferase deficiency: a treatable metabolic encephalomyopathy. Neurology 75: 186-188, 2010. [PubMed: 20625172] [Full Text: https://doi.org/10.1212/WNL.0b013e3181e7cabd]