Heterozygous <i>OGDH</i> Variants Are Involved in Peripheral Neuropathy With Ataxia and Optical Atrophy

ABSTRACT 2‐oxyglutarate dehydrogenase ( OGDH ) encodes an E1 component of α‐ketoglutarate dehydrogenase complex that plays a pivotal role in the Krebs cycle. Biallelic variants in OGDH have been reported to cause an early‐onset neurodevelopmental and mitochondrial disorder. However, monoallelic OGDH variants have not been associated with human disease. Here, we identified de novo c.1909C&gt;T (p.Arg637Trp) and heterozygous c.162T&gt;G (p.Ser54Arg) variants in OGDH in unrelated individuals exhibiting late‐onset neurological phenotypes, characterized by cerebellar ataxia, peripheral neuropathy and optic atrophy. In silico protein structure predictions suggest that the p.Arg637Trp mutation might influence protein function. To determine the functional effects of the OGDH variants in vivo, we generated Drosophila models harboring UAS‐dOgdh ( p.Arg639Trp ) and UAS‐dOgdh ( p.Thr58Arg ) mutations, homologous to the human variants. While the mutant OGDH expression did not lead to defects in development, it did lead to age‐dependent locomotion defects. Further, we found that p.Arg639Trp mutant leads to defective OGDH activity, while p.Thr58Arg causes abnormal proteolytic cleavage and impaired mitochondrial import. These findings suggest that the variants act as dominant‐negative and toxic gain‐of‐function mutations, respectively. Our data provide evidence that monoallelic OGDH variants are involved in late‐onset neurological disease in humans.