GATM – Primary Fanconi Syndrome

Primary Fanconi syndrome is a generalized defect of proximal tubular reabsorption leading to renal losses of glucose, amino acids, phosphate, and bicarbonate. Recent case reports implicate heterozygous missense variants in GATM as a cause of autosomal dominant primary Fanconi syndrome (Primary Fanconi syndrome). Clinical features include leg pain, hypophosphatemic rickets, and progressive kidney failure.

Genetic evidence comprises three unrelated probands harboring heterozygous missense variants in GATM: a family with mother–daughter segregation of c.965G>C (p.Arg322Pro) and an additional sporadic case presenting with hypophosphatemic rickets (PMID:36148635; PMID:38876250). The c.965G>C (p.Arg322Pro) variant disrupts a conserved active-site residue and is absent from population databases.

Segregation data include one affected first-degree relative in a single kindred, corroborating autosomal dominant transmission. No conflicting reports have been published to date.

Functional characterization through molecular dynamics simulations confirms a unique dynamic signature for Arg322Pro correlating with two previously identified pathogenic variants. Complementary site-directed mutagenesis of residue Arg322 (R322E) abolishes catalytic activity of AGAT in vitro, establishing loss of function as the likely pathogenic mechanism (PMID:36148635; PMID:9266688).

Integration of genetic, segregation, and experimental data supports a moderate clinical validity classification. Routine screening of GATM should be considered in children and adults with unexplained Fanconi syndrome to guide prognosis and family planning.

Key Take-home: Heterozygous GATM missense variants, notably p.Arg322Pro, cause autosomal dominant primary Fanconi syndrome via disruption of AGAT catalytic function, warranting inclusion of GATM in diagnostic gene panels.

References

• Clinical genetics • 2023 • A novel variant in GATM causes idiopathic renal Fanconi syndrome and predicts progression to end-stage kidney disease. PMID:36148635
• Clinica chimica acta; international journal of clinical chemistry • 2024 • Complex phenotype in Fanconi renotubular syndrome type 1: Hypophosphatemic rickets as the predominant presentation. PMID:38876250
• European journal of biochemistry • 1997 • Substrate binding and catalysis by L-arginine:glycine amidinotransferase--a mutagenesis and crystallographic study. PMID:9266688

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