HGNC Approved Gene Symbol: GAMT
SNOMEDCT: 124239003;
Cytogenetic location: 19p13.3 Genomic coordinates (GRCh38) : 19:1,397,026-1,401,542 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 19p13.3 | Cerebral creatine deficiency syndrome 2 | 612736 | Autosomal recessive | 3 |
Amidinotransferase converts glycine to guanidinoacetate; guanidinoacetate methyltransferase (GAMT) converts the latter to creatine with S-adenosylmethionine as the methyl donor.
Isbrandt and von Figura (1995) isolated the cDNA of human GAMT from a liver cDNA library with the aid of a partial cDNA of rat GAMT. It contained an open reading frame of 711 nucleotides. Stockler et al. (1996) used this cDNA as a probe for Northern blot analysis of RNA from liver, leukocytes, and fibroblasts of controls. They detected a single GAMT-RNA species of 1.1 kb in all 3 tissues. In leukocytes and fibroblasts, the frequencies of GAMT-RNA were 5- and 17-fold lower, respectively, than in liver.
By somatic cell hybridization and radiation hybrid analysis, Chae et al. (1998) mapped the GAMT gene to chromosome 19p13.3. By interspecific backcross analysis, they mapped the mouse Gamt gene to chromosome 10.
Stockler et al. (1996) studied 2 patients with cerebral creatine deficiency syndrome-2 (CCDS2; 612736) resulting from GAMT deficiency. Patient 1 had inherited from his father a GAMT allele with a 327G-A mutation (601240.0001) and from his mother an allele with insertion of 13 bp after nucleotide 309 (601240.0002). Patient 2 was homozygous for the 327G-A mutation. The parents of both patients were heterozygous for the 327G-A mutation. (The numbering of nucleotides followed the sequence reported by Isbrandt and von Figura (1995).) The 327G-A mutation occupied position -1 of the 5-prime splice site of what was thought to be intron 2. The G in this position is known to be critical for the stability of basepairing between the splice site and the complementary region of U1snRNA and is a frequent target of mutations of 5-prime splice sites. The mutation resulted in the formation of 2 transcripts in each of the 2 patients. The 13-bp insertion within exon 2 in patient 1 is a direct repeat, which suggested to Stockler et al. (1996) that it may have arisen from slipped mispairing during replication. This allele likewise produced 2 alternative transcripts. Patients 1 and 2 were of German and Turkish extraction, respectively.
In 3 family members and an isolated patient with GAMT deficiency, Caldeira Araujo et al. (2005) identified mutations in the GAMT gene (601240.0003-601240.0004, respectively).
In 2 infants with GAMT deficiency, Hart et al. (2021) identified homozygous or compound heterozygous mutations in the GAMT gene (601240.0006-601240.0008). Both infants were initially identified by newborn screening which showed elevated guanidinoacetate level on a bloodspot.
Schmidt et al. (2004) generated a knockout mouse model for GAMT deficiency by gene targeting in embryonic stem cells. Gamt -/- mice had markedly increased guanidinoacetate (GAA) and reduced creatine and creatinine levels in brain, serum, and urine, similar to human GAMT patients. In vivo 31P magnetic resonance spectroscopy showed high levels of PGAA and reduced levels of creatine phosphate in heart, skeletal muscle, and brain. GAMT deficiency was associated with increased neonatal mortality, muscular hypotonia, decreased male fertility, and a non-leptin-mediated lifelong reduction in body weight due to reduced body fat mass.
The report by Ide et al. (2009) that GAMT is critical for the adaptive response to nutrient stress was retracted by the authors.
In a child of German extraction with a severe neurologic syndrome due to cerebral creatine deficiency syndrome-2 (CCDS2; 612736), Stockler et al. (1996) demonstrated compound heterozygosity for a G-to-A transition in the last nucleotide of exon 2 (nucleotide 327) and a direct 13-bp duplication in exon 2 of the GAMT gene (601240.0002). A second child of Turkish extraction was homozygous for the 327G-A mutation. The mutations resulted in the generation of alternative transcripts for the gene.
Schulze et al. (1997) found this mutation in homozygosity in a female infant with GAMT deficiency born of Kurdish first-cousin parents.
For discussion of the 13-bp duplication in exon 2 of the GAMT gene (309dup13) that was found in compound heterozygous state in a patient with a severe neurologic syndrome due to cerebral creatine deficiency syndrome-2 (CCDS2; 612736) by Stockler et al. (1996), see 601240.0001.
In 2 sisters and their male third cousin from a relatively small community in Portugal with cerebral creatine deficiency syndrome-2 (CCDS2; 612736), Caldeira Araujo et al. (2005) identified a homozygous 59G-C transversion in exon 1 of the GAMT gene, resulting in a trp20-to-ser (W20S) substitution.
Almeida et al. (2007) noted that of the 10 reported Portuguese patients with CCDS2, the W20S mutation was found in homozygosity in 8 and in compound heterozygosity in 1. They found that the variant had an overall carrier rate in Portugal of 0.8%, suggesting a founder effect.
In an isolated case of cerebral creatine deficiency syndrome-2 (CCDS2; 612736) from a relatively small community in Portugal, Caldeira Araujo et al. (2005) identified a homozygous 506G-A transition in exon 5 of the GAMT gene, resulting in a cys169-to-tyr (C169Y) substitution.
In a North African patient with cerebral creatine deficiency syndrome-2 and severe mental retardation (CCDS2; 612736), born of consanguineous parents, Lion-Francois et al. (2006) identified a 148A-C transversion in the GAMT gene, resulting in a met50-to-leu (M50L) substitution. The patient had delayed onset of walking, seizures, and autistic features.
In an infant with cerebral creatine deficiency syndrome-2 (CCDS2; 612736), Hart et al. (2021) identified homozygosity for a 1-bp duplication (c.609dupG) in the GAMT gene, predicted to result in a frameshift and extension of the protein beyond the canonical stop site (Arg204GlufsTer63). The mutation was identified by sequencing of the GAMT gene. The patient was initially identified by abnormal newborn screening showing an elevated guanidinoacetate level on a bloodspot. A 6-year-old sib of this patient was noted to have developmental delay, no speech, and hypotonia of unknown etiology; molecular analysis confirmed that the sib was homozygous for the c.609dupG mutation.
In an infant with cerebral creatine deficiency syndrome-2 (CCDS2; 612736), Hart et al. (2021) identified compound heterozygosity for 2 mutations in the GAMT gene, a c.522G-A transition, resulting in a trp174-to-ter (W174X) substitution, and a c.327G-A transition, predicted to cause a splicing abnormality. The mutations were identified by sequencing of the GAMT gene, and the parents were shown to be carriers. The c.327G-A transition, which affected a consensus splice site, was predicted to cause an insertion of 44 nucleotides or deletion of 146 nucleotides, both resulting in a frameshift and premature termination. The patient was initially identified by abnormal newborn screening showing an elevated guanidinoacetate level on a bloodspot.
For discussion of the c.327G-A transition in the GAMT gene, predicted to cause a splicing abnormality, that was found in compound heterozygous state in an infant with cerebral creatine deficiency syndrome-2 (CCDS2; 612736) by Hart et al. (2021), see 601240.0007.
Almeida, L. S., Vilarinho, L., Darmin, P. S., Rosenberg, E. H., Martinez-Munoz, C., Jakobs, C., Salomons, G. S. A prevalent pathogenic GAMT mutation (c.59G-C) in Portugal. Molec. Genet. Metab. 91: 1-6, 2007. [PubMed: 17336114] [Full Text: https://doi.org/10.1016/j.ymgme.2007.01.005]
Caldeira Araujo, H., Smit, W., Verhoeven, N. M., Salomons, G. S., Silva, S., Vasconcelos, R., Tomas, H., Tavares de Almeida, I., Jakobs, C., Duran, M. Guanidinoacetate methyltransferase deficiency identified in adults and a child with mental retardation. Am. J. Med. Genet. 133A: 122-127, 2005. [PubMed: 15651030] [Full Text: https://doi.org/10.1002/ajmg.a.30226]
Chae, Y.-J., Chung, C.-E., Kim, B.-J., Lee, M.-H., Lee, H. The gene encoding guanidinoacetate methyltransferase (GAMT) maps to human chromosome 19 at band p13.3 and to mouse chromosome 10. Genomics 49: 162-164, 1998. [PubMed: 9570966] [Full Text: https://doi.org/10.1006/geno.1998.5236]
Hart, K., Rohrwasser, A., Wallis, H., Golsan, H., Shao, J., Anderson, 0 T., Wang, X., Szabo-Fresnais, N., Morrissey, M., Kay, D. M., Wojcik, M., Galvin-Parton, P. A., Longo, N., Caggana, M., Pasquali, M. Prospective identification by neonatal screening of patients with guanidinoacetate methyltransferase deficiency. Molec. Genet. Metab. 134: 60-64, 2021. [PubMed: 34389248] [Full Text: https://doi.org/10.1016/j.ymgme.2021.07.012]
Ide, T., Brown-Endres, L., Chu, K., Ongusaha, P. P., Ohtsuka, T., El-Deiry, W. S., Aaronson, S. A., Lee, S. W. GAMT, a p53-inducible modulator of apoptosis, is critical for the adaptive response to nutrient stress. Molec. Cell 36: 379-392, 2009. Note: Retraction: Molec. Cell 51: 552 only, 2013. [PubMed: 19917247] [Full Text: https://doi.org/10.1016/j.molcel.2009.09.031]
Isbrandt, D., von Figura, K. Cloning and sequence analysis of human guanidinoacetate N-methyltransferase cDNA. Biochim. Biophys. Acta 1264: 265-267, 1995. [PubMed: 8547310] [Full Text: https://doi.org/10.1016/0167-4781(95)00184-0]
Lion-Francois, L., Cheillan, D., Pitelet, G., Acquaviva-Bourdain, C., Bussy, G., Cotton, F., Guibaud, L., Gerard, D., Rivier, C., Vianey-Saban, C., Jakobs, C., Salomons, G. S., des Portes, V. High frequency of creatine deficiency syndromes in patients with unexplained mental retardation. Neurology 67: 1713-1714, 2006. [PubMed: 17101918] [Full Text: https://doi.org/10.1212/01.wnl.0000239153.39710.81]
Schmidt, A., Marescau, B., Boehm, E. A., Renema, W. K. J., Peco, R., Das, A., Steinfeld, R., Chan, S., Wallis, J., Davidoff, M., Ullrich, K., Waldschutz, R., Heerschap, A., De Deyn, P. P., Neubauer, S., Isbrandt, D. Severely altered guanidino compound levels, disturbed body weight homeostasis and impaired fertility in a mouse model of guanidinoacetate N-methyltransferase (GAMT) deficiency. Hum. Molec. Genet. 13: 905-921, 2004. [PubMed: 15028668] [Full Text: https://doi.org/10.1093/hmg/ddh112]
Schulze, A., Hess, T., Wevers, R., Mayatepek, E., Bachert, P., Marescau, B., Knopp, M. V., De Deyn, P. P., Bremer, H. J., Rating, D. Creatine deficiency syndrome caused by guanidinoacetate methyltransferase deficiency: diagnostic tools for a new inborn error of metabolism. J. Pediat. 131: 626-631, 1997. [PubMed: 9386672] [Full Text: https://doi.org/10.1016/s0022-3476(97)70075-1]
Stockler, S., Isbrandt, D., Hanefeld, F., Schmidt, B., von Figura, K. Guanidinoacetate methyltransferase deficiency: the first inborn error of creatine metabolism in man. Am. J. Hum. Genet. 58: 914-922, 1996. [PubMed: 8651275]