954B Poster - 15. Models of human disease
Friday April 08, 2:00 PM - 4:00 PM

Authors:
Zheng Yie Yap ¹; Stephanie Efthymiou ²; Simone Seiffert ³; Karen Vargas Parra ¹; Sukyeong Lee ⁴; Alessia Nasca ⁵; Reza Maroofian ²; Isabelle Schrauwen ⁶; Manuela Pendziwiat ⁷; Sunhee Jung ⁸; Pasquale Striano ⁹; Kshitij Mankad ¹⁰; Barbara Vona ¹¹; Sanmati Cuddapah ¹²; Srinitya Gannavarapu ¹³; Costanza Lamperti ⁵; Andrea Legati ⁵; Vincenzo Salpietro ⁹; Sarah von Spiczak ⁷; Abigail Sandoval ¹; Massimo Zeviani ¹⁴; Adi Reich ¹⁵; Cholsoon Jang ⁸; Ingo Helbig ^7,16,17; Tahsin Stefan Barakat ¹⁸; Daniele Ghezzi ^5,19; Suzanne M Leal ⁶; Yvonne Weber ^3,20; Henry Houlden ²; Wan Hee Yoon ¹

Affiliations:
1) Oklahoma Medical Research Foundation, OKC, OK, USA; 2) UCL Queen Square Institute of Neurology, London, UK; 3) University of Tübingen, Tübingen, Germany ; 4) Baylor College of Medicine, Houston, TX, USA; 5) Fondazione IRCCS Istituto Neurologico "Carlo Besta", Milan, Italy; 6) Columbia University Medical Center, New York, NY, USA; 7) Christian-Albrechts-University of Kiel, Kiel, Germany; 8) University of California Irvine, Irvine, CA, USA; 9) University of Genoa, Genoa, Italy; 10) Great Ormond Street Hospital for Children, London, UK; 11) Eberhard Karls University, Tübingen, Germany; 12) Children's Hospital of Philadelphia, Philadelphia, PA, USA; 13) Western University, London, ON, Canada; 14) University of Padova, Padova, Italy; 15) GeneDx, Gaithersburg, MD, USA; 16) Children’s Hospital of Philadelphia; 17) University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA; 18) Erasmus University Medical Center, Rotterdam, Netherlands; 19) University of Milan, Milan, Italy ; 20) University of Aachen, Aachen, Germany

Keywords:
b. neural disorder; t. other (mitochondrial metabolism )

The 2-oxoglutarate dehydrogenase-like protein (OGDHL) 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 biallelic 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, p.Arg299Gly), three compound heterozygous single nucleotide variants (p.Arg673Gln/p.Val488Val, p.Phe734Ser/p.Ala327Val, p.Trp220Cys/p.Asp491Val), one homozygous frameshift variant (p.Cys553Leufs*16), and one homozygous stopgain 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, which was fully rescued by expression of wild-type dOgdh. Studies using the Drosophila system indicate that 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 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 biallelic variants in OGDHL are pathogenic, leading to a Mendelian neurodevelopmental disease in humans.