OAT – Ornithine Aminotransferase Deficiency

Ornithine aminotransferase (OAT) is a mitochondrial matrix enzyme critical for ornithine catabolism. Biallelic pathogenic variants in OAT cause ornithine aminotransferase deficiency (gyrate atrophy, OMIM:258870), an autosomal recessive chorioretinal dystrophy characterized by progressive visual loss, chorioretinal degeneration, and systemic hyperornithinemia (PMID:2220818). Early-onset night blindness and hyperornithinemia support a biochemical diagnosis that is confirmed by molecular genetic testing.

Autosomal recessive inheritance is established by reports of homozygous and compound heterozygous OAT mutations segregating in multiple sibships. Molecular screening in 11 unrelated probands identified six missense, three nonsense, one 2-bp frameshift, and one splice-site mutation, with segregation of variants in affected siblings and carrier parents (PMID:8125717). The c.472_486del (p.Tyr158_Gly162del) variant exemplifies an in‐frame deletion in exon 5, resulting in loss of a conserved pentapeptide.

The variant spectrum includes splice-site deletions (e.g., c.425-4_429del), nonsense alleles (e.g., c.627T>A (p.Tyr209Ter)), and missense substitutions (e.g., c.268C>G (p.Gln90Glu)). Founder alleles have been reported in Finnish and Japanese populations, whereas other variants (e.g., c.248G>A (p.Ser83Asn)) recur in consanguineous pedigrees. Functional assays reveal that most missense alleles markedly reduce OAT activity, while premature termination codons trigger nonsense‐mediated mRNA decay (PMID:1609808).

Mechanistic studies demonstrate that certain missense mutations disturb mitochondrial targeting (e.g., p.Gln90Glu) or promote apo-enzyme aggregation (e.g., p.Val332Met), confirming loss‐of‐function as the pathogenic mechanism (PMID:7668253). In vitro yeast and lymphocyte enzyme assays show residual activity correlating variably with clinical severity. Pyridoxine (vitamin B6)‐responsive alleles, such as p.Ala226Val, increase OAT activity upon PLP supplementation, guiding therapeutic decisions (PMID:7887415).

Longitudinal follow-up studies demonstrate that arginine-restricted or low-protein diets significantly reduce plasma ornithine levels and slow chorioretinal degeneration, especially when initiated in childhood (PMID:15159649). Vitamin B6 supplementation yields functional improvement in responsive genotypes, underscoring the value of genotype-guided management.

Integration of genetic and functional data supports a Definitive gene–disease association. Clinical genetic testing for OAT variants informs therapeutic options, including dietary modification and pyridoxine supplementation. Early molecular diagnosis is essential for preserving vision and guiding family counseling.

References

• American Journal of Human Genetics | 1990 | Splicing defect at the ornithine aminotransferase (OAT) locus in gyrate atrophy. PMID:2220818
• Investigative Ophthalmology & Visual Science | 1994 | Rapid and efficient molecular analysis of gyrate atrophy using denaturing gradient gel electrophoresis. PMID:8125717
• American Journal of Human Genetics | 1995 | A single amino acid substitution within the mature sequence of ornithine aminotransferase obstructs mitochondrial entry of the precursor. PMID:7668253
• American Journal of Human Genetics | 1995 | Pyridoxine-responsive gyrate atrophy of the choroid and retina: clinical and biochemical correlates of the mutation A226V. PMID:7887415
• Journal of Inherited Metabolic Disease | 2004 | Low-protein diet and progression of retinal degeneration in gyrate atrophy of the choroid and retina: a twenty-six-year follow-up. PMID:15159649

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