GNMT – Glycine N-methyltransferase Deficiency

Glycine N-methyltransferase (GNMT) is a key hepatic enzyme regulating S-adenosylmethionine metabolism. Biallelic loss-of-function variants in GNMT cause an autosomal recessive dysmethylating liver disorder, glycine N-methyltransferase deficiency, characterized by persistent hypermethioninemia and mild hepatopathy. To date, only four patients have been described worldwide ([PMID:14739680]; [PMID:27207470]). Early reports suggested a benign course, but recent evidence highlights potential diagnostic pitfalls and variable clinical severity.

Genetic evidence comprises four unrelated probands homozygous or compound heterozygous for rare missense variants. The prototypical mutation c.422A>G (p.Asn141Ser) was identified in a Greek boy with persistent hypermethioninemia and mild transaminase elevations ([PMID:14739680]). No protein-truncating or deep-intronic alleles have been reported, and no additional affected relatives beyond index cases have been documented.

Segregation analysis is limited to carrier status in parents, consistent with an autosomal recessive inheritance mode. No multiplex families or further segregation data are available, and the genetic evidence currently rests on isolated case reports without extended pedigree support.

Functional assays in recombinant systems demonstrate that the p.Asn141Ser variant retains <0.5% of wild-type catalytic activity ([PMID:14651980]). Additional missense mutants—p.His176Asn (75% activity) and p.Leu49Pro (10% activity)—show graded loss of function concordant with biochemical phenotypes. Biophysical studies further reveal that p.His176Asn markedly destabilizes the GNMT tetramer, reducing dissociation and unfolding free energies ([PMID:17660255]).

The collective data support a loss-of-function mechanism whereby deficient GNMT activity leads to impaired S-adenosylmethionine clearance, dysmethylation, and sustained hypermethioninemia. Clinical features include hypermethioninemia (HP:0003235), mild hepatomegaly, and chronic transaminase elevation; long-term prognosis remains uncertain ([PMID:27207470]).

References

• Journal of inherited metabolic disease • 2003 • Glycine N-methyltransferase deficiency: a new patient with a novel mutation. PMID:14739680
• JIMD reports • 2017 • Glycine N-Methyltransferase Deficiency: A Member of Dysmethylating Liver Disorders? PMID:27207470
• Biochemical and biophysical research communications • 2003 • Effect of naturally occurring mutations in human glycine N-methyltransferase on activity and conformation. PMID:14651980
• Protein science : a publication of the Protein Society • 2007 • Destabilization of human glycine N-methyltransferase by H176N mutation. PMID:17660255

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