Abstract
The 2-oxoglutarate dehydrogenase-like (OGDHL) protein is a rate-limiting enzyme in the Krebs cycle that plays a pivotal role in mitochondrial metabolism.
OGDHL
expression is restricted mainly to the brain in humans. Here, we report nine individuals from eight unrelated families carrying bi-allelic variants in
OGDHL
with a range of neurological and neurodevelopmental phenotypes including epilepsy, hearing loss, visual impairment, gait ataxia, microcephaly, and hypoplastic corpus callosum. The variants include three homozygous missense variants (p.Pro852Ala, p.Arg244Trp, and p.Arg299Gly), three compound heterozygous single-nucleotide variants (p.Arg673Gln/p.Val488Val, p.Phe734Ser/p.Ala327Val, and p.Trp220Cys/p.Asp491Val), one homozygous frameshift variant (p.Cys553Leufs
∗
16), and one homozygous stop-gain variant (p.Arg440Ter). To support the pathogenicity of the variants, we developed a novel CRISPR-Cas9-mediated tissue-specific knockout with cDNA rescue system for
dOgdh,
the
Drosophila
ortholog of human
OGDHL
. Pan-neuronal knockout of
dOgdh
led to developmental lethality as well as defects in Krebs cycle metabolism, which was fully rescued by expression of wild-type
dOgdh
. Studies using the
Drosophila
system indicate that p.Arg673Gln, p.Phe734Ser, and p.Arg299Gly are severe loss-of-function alleles, leading to developmental lethality, whereas p.Pro852Ala, p.Ala327Val, p.Trp220Cys, p.Asp491Val, and p.Arg244Trp are hypomorphic alleles, causing behavioral defects. Transcript analysis from fibroblasts obtained from the individual carrying the synonymous variant (c.1464T>C [p.Val488Val]) in family 2 showed that the synonymous variant affects splicing of exon 11 in
OGDHL
. Human neuronal cells with
OGDHL
knockout exhibited defects in mitochondrial respiration, indicating the essential role of
OGDHL
in mitochondrial metabolism in humans. Together, our data establish that the bi-allelic variants in
OGDHL
are pathogenic, leading to a Mendelian neurodevelopmental disease in humans.