A biallelic pathogenic variant in the OGDH gene results in a neurological disorder with features of a mitochondrial disease

Abstract

2‐Oxoglutarate dehydrogenase (OGDH) is a rate‐limiting enzyme in the mitochondrial TCA cycle, encoded by the OGDH gene. α‐Ketoglutarate dehydrogenase (OGDH) deficiency was previously reported in association with developmental delay, hypotonia, and movement disorders and metabolic decompensation, with no genetic data provided. Using whole exome sequencing, we identified two individuals carrying a homozygous missense variant c.959A>G (p.N320S) in the OGDH gene. These individuals presented with global developmental delay, elevated lactate, ataxia and seizure. Fibroblast analysis and modeling of the mutation in Drosophila were used to evaluate pathogenicity of the variant. Skin fibroblasts from subject # 2 showed a decrease in both OGDH protein and enzyme activity. Transfection of human OGDH cDNA in HEK293 cells carrying p.N320S also produced significantly lower protein levels compared to those with wild‐type cDNA. Loss of Drosophila Ogdh (dOgdh) caused early developmental lethality, rescued by expressing wild‐type dOgdh (dOgdhWT) or human OGDH (OGDHWT) cDNA. In contrast, expression to the mutant OGDH (OGDHN320S) or dOgdh carrying homologous mutations to human OGDH p.N320S variant (dOgdhN324S) failed to rescue lethality of dOgdh null mutants. Knockdown of dOgdh in the nervous system resulted in locomotion defects which were rescued by dOgdhWT expression but not by dOgdhN324S expression. Collectively, the results indicate that c.959A>G variant in OGDH leads to an amino acid change (p.N320S) causing a severe loss of OGDH protein function. Our study establishes in the first time a genetic link between an OGDH gene mutation and OGDH deficiency.

Toward an Understanding of the Structural and Mechanistic Aspects of Protein-Protein Interactions in 2-Oxoacid Dehydrogenase Complexes

“…Diminished OGDHc activity and mitochondrial abnormalities have been correlated with numerous neurodegenerative disorders, including Alzheimer’s disease, however, a link between reductions in the mitochondrial TCA cycle enzymes and (neuro) degeneration has not been established so far [ 1 , 2 , 3 , 4 ]. Recently, a biallelic pathogenic variant in OGDH gene leading to deficient 2-oxoglutarate dehydrogenase (E1o, the first component of the OGDHc, also known as OGDH) was reported in individuals with a neurological disorder resembling mitochondrial disease [ 5 ]. While rare in OGDH , whole-exome sequencing and rare variant burden analysis determined an overabundance of putative, potentially damaging mutations in the OGDHL (OGDH-like) and DHTKD1 genes across multiple patients with eosinophilic esophagitis (EoE), a chronic allergic disorder that presents in infancy and in adulthood [ 6 ].…”

Citrate Synthase and OGDH as Potential Biomarkers of Atherosclerosis under Chronic Stress

“…Citrate synthase [ 12 ] and oxoglutarate dehydrogenase (OGDH) [ 13 ] catalyze the condensation of acetyl-CoA from glycolysis or other dissimilatory reactions with oxaloacetate to synthesize citric acid. They are the rate-limiting enzymes in the mitochondrial tricarboxylic acid (TCA) cycle and participate in many important biochemical processes.…”

OGDH is involved in sepsis induced acute lung injury through the MAPK pathway

“…Studies have shown that OGDH is associated with cell damage after cardiac ischemia perfusion (10), and has previously been reported to be associated with developmental delay, hypotonia, dyspraxia, and metabolic decompensation (11)(12)(13)(14). Recently, mutations in OGDH have been reported to cause global growth retardation, lactic acid elevation, ataxia, and seizures (15). However, there is no clear evidence that changes in OGDH expression are associated with various types of inflammation.…”