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.
| Original language | English |
|---|---|
| Pages (from-to) | 2368-2384 |
| Number of pages | 17 |
| Journal | American Journal of Human Genetics |
| Volume | 108 |
| Issue number | 12 |
| DOIs | |
| Publication status | Published - 2 Dec 2021 |
Bibliographical note
Funding Information:We thank all individuals and relatives for consent to be part of the study. Families 5?8 were collected as part of the SYNaPS Study Group collaboration funded by The Wellcome Trust and strategic award (Synaptopathies) funding (WT093205 MA and WT104033AIA), and research was conducted as part of the Queen Square Genomics group at University College London, supported by the National Institute for Health Research University College London Hospitals Biomedical Research Centre. We thank former and present Yoon lab members for their input during investigations, particularly Madison Chilian, Yohan Park, David Seo, and Jae Sun Kang. We thank Holly Van Remmen for her support of Seahorse assays. We thank Scott Plafker for his helpful advices during investigation. We thank Hugo Bellen for his help to initiate this study. We thank the ?Cell line and DNA Bank of Genetic Movement Disorders and Mitochondrial Diseases? of the Telethon Network of Genetic Biobanks (grant GTB12001J) and Eurobiobank Network, which supplied biological specimens for family 2. C.L. and D.G. are members of the European Reference Network for Rare Neuromuscular Diseases (ERN EURO-NMD). W.H.Y. is supported by the National Institute of General Medical Sciences (5 P20 GM103636-08) and the National Institute of Neurological Disorders and Stroke (1R01 NS121298-01) of the National Institutes of Health. W.H.Y. was also supported by Presbyterian Health Foundation (PHF 4431-04-04-0 and PHF 4411-05-07-0). H.H. is funded by the MRC (MR/S01165X/1, MR/S005021/1, G0601943), the National Institute for Health Research University College London Hospitals Biomedical Research Centre, Rosetree Trust, Ataxia UK, MSA Trust, Brain Research UK, Sparks GOSH Charity, Muscular Dystrophy UK (MDUK), and Muscular Dystrophy Association (MDA USA). Y.W. was funded by the German Research Foundation (DFG; WE4896/3-1) by the DFG/FNR INTER Research Unit FOR2715 (WE4896/4-1) Treat-ION grant (01GM1907) (continued in supplemental acknowledgments). I.H. serves on the Scientific Advisory Board of Biogen. A.R. is an employee of GeneDx. The remaining authors declare no competing interests.
Funding Information:
We thank all individuals and relatives for consent to be part of the study. Families 5–8 were collected as part of the SYNaPS Study Group collaboration funded by The Wellcome Trust and strategic award (Synaptopathies) funding ( WT093205 MA and WT104033AIA ), and research was conducted as part of the Queen Square Genomics group at University College London, supported by the National Institute for Health Research University College London Hospitals Biomedical Research Centre . We thank former and present Yoon lab members for their input during investigations, particularly Madison Chilian, Yohan Park, David Seo, and Jae Sun Kang. We thank Holly Van Remmen for her support of Seahorse assays. We thank Scott Plafker for his helpful advices during investigation. We thank Hugo Bellen for his help to initiate this study. We thank the “Cell line and DNA Bank of Genetic Movement Disorders and Mitochondrial Diseases” of the Telethon Network of Genetic Biobanks (grant GTB12001J ) and Eurobiobank Network, which supplied biological specimens for family 2. C.L. and D.G. are members of the European Reference Network for Rare Neuromuscular Diseases (ERN EURO-NMD). W.H.Y. is supported by the National Institute of General Medical Sciences ( 5 P20 GM103636-08 ) and the National Institute of Neurological Disorders and Stroke ( 1R01 NS121298-01 ) of the National Institutes of Health. W.H.Y. was also supported by Presbyterian Health Foundation ( PHF 4431-04-04-0 and PHF 4411-05-07-0 ). H.H. is funded by the MRC ( MR/S01165X/1 , MR/S005021/1 , G0601943 ), the National Institute for Health Research University College London Hospitals Biomedical Research Centre, Rosetree Trust , Ataxia UK , MSA Trust , Brain Research UK , Sparks GOSH Charity , Muscular Dystrophy UK (MDUK), and Muscular Dystrophy Association (MDA USA). Y.W. was funded by the German Research Foundation (DFG; WE4896/3-1 ) by the DFG/FNR INTER Research Unit FOR2715 ( WE4896/4-1 ) Treat-ION grant ( 01GM1907 ) (continued in supplemental acknowledgments ).
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