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Bi-allelic variants in OGDHL cause a neurodevelopmental spectrum disease featuring epilepsy, hearing loss, visual impairment, and ataxia.
Yap, Zheng Yie; Efthymiou, Stephanie; Seiffert, Simone; Vargas Parra, Karen; Lee, Sukyeong; Nasca, Alessia; Maroofian, Reza; Schrauwen, Isabelle; Pendziwiat, Manuela; Jung, Sunhee; Bhoj, Elizabeth; Striano, Pasquale; Mankad, Kshitij; Vona, Barbara; Cuddapah, Sanmati; Wagner, Anja; Alvi, Javeria Raza; Davoudi-Dehaghani, Elham; Fallah, Mohammad-Sadegh; Gannavarapu, Srinitya; Lamperti, Costanza; Legati, Andrea; Murtaza, Bibi Nazia; Nadeem, Muhammad Shahid; Rehman, Mujaddad Ur; Saeidi, Kolsoum; Salpietro, Vincenzo; von Spiczak, Sarah; Sandoval, Abigail; Zeinali, Sirous; Zeviani, Massimo; Reich, Adi; Jang, Cholsoon; Helbig, Ingo; Barakat, Tahsin Stefan; Ghezzi, Daniele; Leal, Suzanne M; Weber, Yvonne; Houlden, Henry; Yoon, Wan Hee.
Afiliação
  • Yap ZY; Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA.
  • Efthymiou S; Department of Neuromuscular Disorders, UCL Queen Square Institute of Neurology, London WC1N 3BG, UK.
  • Seiffert S; Department of Neurology and Epileptology, Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen 72076, Germany.
  • Vargas Parra K; Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA.
  • Lee S; Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
  • Nasca A; Unit of Medical Genetics and Neurogenetics, Fondazione IRCCS Istituto Neurologico "Carlo Besta," via Temolo 4, 20126 Milan, Italy.
  • Maroofian R; Department of Neuromuscular Disorders, UCL Queen Square Institute of Neurology, London WC1N 3BG, UK.
  • Schrauwen I; Center for Statistical Genetics, Gertrude H. Sergievsky Center, and the Department of Neurology, Columbia University Medical Center, New York, NY 10032, USA.
  • Pendziwiat M; Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel 24105, Germany.
  • Jung S; Department of Biological Chemistry, University of California, Irvine, Irvine, CA 92697, USA.
  • Bhoj E; Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
  • Striano P; Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, 16124 Genoa, Italy; Pediatric Neurology and Muscular Diseases Unit, IRCCS, Istituto "Giannina Gaslini," Genoa 16123, Italy.
  • Mankad K; Neuroradiology Unit, Great Ormond Street Hospital for Children, London WC1N3JH, UK.
  • Vona B; Department of Otolaryngology-Head and Neck Surgery, Tübingen Hearing Research Center, Eberhard Karls University, 72076 Tübingen, Germany.
  • Cuddapah S; Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
  • Wagner A; Department of Clinical Genetics, Erasmus University Medical Center, Erasmus MC Cancer Institute, 3000 Rotterdam, the Netherlands.
  • Alvi JR; Department of Pediatric Neurology, Institute of Child Health, Children Hospital Lahore, Lahore 54600, Pakistan.
  • Davoudi-Dehaghani E; Department of Molecular Medicine, Biotechnology Research Center, Pasteur Institute of Iran, Tehran 1316943551, Iran.
  • Fallah MS; Department of Medical Genetics, Kawsar Human Genetics Research Center, Tehran 15956-45513, Iran.
  • Gannavarapu S; Department of Pathology and Laboratory Medicine, Western University, London, ON N6A 5C1, Canada.
  • Lamperti C; Unit of Medical Genetics and Neurogenetics, Fondazione IRCCS Istituto Neurologico "Carlo Besta," via Temolo 4, 20126 Milan, Italy.
  • Legati A; Unit of Medical Genetics and Neurogenetics, Fondazione IRCCS Istituto Neurologico "Carlo Besta," via Temolo 4, 20126 Milan, Italy.
  • Murtaza BN; Department of Zoology, Abbottabad University of Science and Technology, Abbottabad 22500, Pakistan.
  • Nadeem MS; Department of Biochemistry, King Abdulaziz University, Jeddah 21589, Saudi Arabia.
  • Rehman MU; Department of Microbiology, Abbottabad University of Science and Technology, Abbottabad 22500, Pakistan.
  • Saeidi K; Neuroscience Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman 7616914115, Iran.
  • Salpietro V; Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, 16124 Genoa, Italy; Pediatric Neurology and Muscular Diseases Unit, IRCCS, Istituto "Giannina Gaslini," Genoa 16123, Italy.
  • von Spiczak S; Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel 24105, Germany; DRK-Northern German Epilepsy Centre for Children and Adolescents, 24223 Schwentinental-Raisdorf, Germany.
  • Sandoval A; Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA.
  • Zeinali S; Department of Molecular Medicine, Biotechnology Research Center, Pasteur Institute of Iran, Tehran 1316943551, Iran.
  • Zeviani M; Department of Neurosciences, University of Padova, via Giustiniani 2, Padova 35128, Italy.
  • Reich A; GeneDx, Gaithersburg, MD 20877, USA.
  • Jang C; Department of Biological Chemistry, University of California, Irvine, Irvine, CA 92697, USA.
  • Helbig I; Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel 24105, Germany; Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; The Epilepsy NeuroGenetics Initiative, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Depa
  • Barakat TS; Department of Clinical Genetics, Erasmus University Medical Center, 3015 Rotterdam, the Netherlands.
  • Ghezzi D; Unit of Medical Genetics and Neurogenetics, Fondazione IRCCS Istituto Neurologico "Carlo Besta," via Temolo 4, 20126 Milan, Italy; Department of Pathophysiology and Transplantation, University of Milan, 20122 Milan, Italy.
  • Leal SM; Center for Statistical Genetics, Gertrude H. Sergievsky Center, and the Department of Neurology, Columbia University Medical Center, New York, NY 10032, USA; Taub Institute for Alzheimer Disease and the Aging Brain, Columbia University Medical Center, New York, NY 10032, USA.
  • Weber Y; Department of Neurology and Epileptology, Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen 72076, Germany; Department of Epileptology and Neurology, University of Aachen, Aachen 52074, Germany.
  • Houlden H; Department of Neuromuscular Disorders, UCL Queen Square Institute of Neurology, London WC1N 3BG, UK.
  • Yoon WH; Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA. Electronic address: wanhee-yoon@omrf.org.
Am J Hum Genet ; 108(12): 2368-2384, 2021 12 02.
Article em En | MEDLINE | ID: mdl-34800363
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.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Ataxia / Transtornos da Visão / Epilepsia / Transtornos do Neurodesenvolvimento / Perda Auditiva / Complexo Cetoglutarato Desidrogenase / Mutação Tipo de estudo: Etiology_studies / Incidence_studies / Observational_studies / Risk_factors_studies Limite: Animals / Child / Female / Humans / Male Idioma: En Revista: Am J Hum Genet Ano de publicação: 2021 Tipo de documento: Article País de afiliação: Estados Unidos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Ataxia / Transtornos da Visão / Epilepsia / Transtornos do Neurodesenvolvimento / Perda Auditiva / Complexo Cetoglutarato Desidrogenase / Mutação Tipo de estudo: Etiology_studies / Incidence_studies / Observational_studies / Risk_factors_studies Limite: Animals / Child / Female / Humans / Male Idioma: En Revista: Am J Hum Genet Ano de publicação: 2021 Tipo de documento: Article País de afiliação: Estados Unidos