GAMT Gene: Guanidinoacetate N-Methyltransferase - Function, Mutations & Related Diseases

The GAMT gene encodes guanidinoacetate N-methyltransferase, an enzyme that catalyzes the final step of creatine biosynthesis, transferring a methyl group from S-adenosylmethionine to guanidinoacetate to form creatine. Creatine is essential for energy storage and transfer in tissues with high energy demands, such as muscle and brain. Loss-of-function mutations in GAMT cause cerebral creatine deficiency syndrome 2 (CCDS2), an autosomal recessive disorder characterized by intellectual disability, epilepsy, movement disorders, and autistic behavior. Diagnosis is based on elevated guanidinoacetate in urine and plasma, and reduced brain creatine on MRS. Treatment includes creatine supplementation, ornithine, and arginine restriction.

Tissue Expression

Cell Line Expression

Hotspot Mutations

Mutation functional classification

• Creatine metabolism (Reactome: R-HSA-71288)

• Glycine

• serine

• and threonine metabolism (KEGG: hsa00260)

• Arginine and proline metabolism (KEGG: hsa00330)

Guanidinoacetate N-methyltransferase (GAMT) is a 236-amino acid cytosolic enzyme that catalyzes the conversion of guanidinoacetate to creatine using S-adenosylmethionine as the methyl donor. The protein is a homodimer, with each subunit containing a methyltransferase domain. GAMT is highly expressed in liver and kidney, with moderate expression in brain, testis, heart, and skeletal muscle. Mutations in GAMT lead to cerebral creatine deficiency syndrome 2, characterized by intellectual disability, epilepsy, movement disorders, and autistic behavior. The enzyme is essential for maintaining cellular energy homeostasis, particularly in tissues with high and fluctuating energy demands.