ArticleActa neuropathologica2020
Loss of UGP2 in brain leads to a severe epileptic encephalopathy, emphasizing that bi-allelic isoform-specific start-loss mutations of essential genes can cause genetic diseases.
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Article in Acta neuropathologica, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 42 papers, 1 of them a synthesis that pooled it.
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42 citing papers in PubMed, 1 synthesis or guideline pooled it, 70 citations in OpenAlex.
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Authors and funding
69 authors at 19 institutions in 11 countries.
Elena PerenthalerDepartment of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam, The Netherlands.
Anita NikoncukDepartment of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam, The Netherlands.
Soheil YousefiDepartment of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam, The Netherlands.
Woutje M BerdowskiDepartment of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam, The Netherlands.
Maysoon AlsagobDepartment of Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh, 11211, Kingdom of Saudi Arabia.
Ivan CapoDepartment for Histology and Embryology, Faculty of Medicine Novi Sad, University of Novi Sad, Novi Sad, Serbia.
Herma C van der LindeDepartment of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam, The Netherlands.
Paul van den BergDepartment of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam, The Netherlands.
Edwin H JacobsDepartment of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam, The Netherlands.
Darija PutarDepartment of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam, The Netherlands.
Mehrnaz GhazviniiPS Cell Core Facility, Erasmus MC University Medical Center, Rotterdam, The Netherlands.
Eleonora AronicaDepartment of (Neuro)Pathology, Amsterdam Neuroscience, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.
Wilfred F J van IJckenCenter for Biomics, Department of Cell Biology, Erasmus MC University Medical Center, Rotterdam, The Netherlands.
Walter G de ValkDepartment of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam, The Netherlands.
Evita Medici-van den HerikDepartment of Neurology, Erasmus MC University Medical Center, Rotterdam, The Netherlands.
Marjon van SlegtenhorstDepartment of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam, The Netherlands.
Lauren BrickDivision of Genetics, McMaster Children's Hospital, Hamilton, ON, L8S 4J9, Canada.
Mariya KozenkoDivision of Genetics, McMaster Children's Hospital, Hamilton, ON, L8S 4J9, Canada.
Jennefer N KohlerDivision of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA, 94035, USA.
Jonathan A BernsteinDivision of Medical Genetics, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, 94035, USA.
Kristin G MonaghanGeneDx, Gaithersburg, MD, 20877, USA.
Amber BegtrupGeneDx, Gaithersburg, MD, 20877, USA.
Rebecca ToreneGeneDx, Gaithersburg, MD, 20877, USA.
Amna Al FutaisiDepartment of Child Health, College of Medicine and Health Sciences, Sultan Qaboos University, Muscat, Oman.
Fathiya Al MurshediGenetic and Developmental Medicine Clinic, Sultan Qaboos University Hospital, Muscat, Oman.
Renjith ManiDepartment of Child Health, College of Medicine and Health Sciences, Sultan Qaboos University, Muscat, Oman.
Faisal Al AzriDepartment of Radiology and Molecular Imaging, Sultan Qaboos University Hospital, Muscat, Oman.
Erik-Jan KamsteegDepartment of Human Genetics, Radboud University Medical Centre, Nijmegen, The Netherlands.
Majid MojarradDepartment of Medical Genetics, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
Atieh EslahiDepartment of Medical Genetics, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
Zaynab KhazaeiGenetic Center of Khorasan Razavi, Mashhad, Iran.
Fateme Massinaei DarmiyanGenetic Counseling Center, Welfare Organization of Sistan and Baluchestan, Zahedan, Iran.
Mohammad DoostiDepartment Medical Genetics, Next Generation Genetic Polyclinic, Mashhad, Iran.
Ehsan Ghayoor KarimianiMolecular and Clinical Sciences Institute, St. George's University of London, Cranmer Terrace, London, SW17 0RE, UK.
Jana VandrovcovaDepartment of Neuromuscular Disorders, UCL Queen Square Institute of Neurology, London, WC1N 3BG, UK.
Faisal ZafarDepartment of Paediatric Neurology, Children's Hospital and Institute of Child Health, Multan, 60000, Pakistan.
Nuzhat RanaDepartment of Paediatric Neurology, Children's Hospital and Institute of Child Health, Multan, 60000, Pakistan.
Krishna K KandaswamyCENTOGENE AG, Rostock, Germany.
Jozef HertecantDepartment of Pediatrics, Tawam Hospital, and College of Medicine and Health Sciences, UAE University, Al-Ain, UAE.
Peter BauerCENTOGENE AG, Rostock, Germany.
Mohammed A AlMuhaizeaDepartment of Neurosciences, King Faisal Specialist Hospital and Research Centre, Riyadh, 11211, Kingdom of Saudi Arabia.
Mustafa A SalihNeurology Division, Department of Pediatrics, College of Medicine, King Saud University, Riyadh, 11461, Kingdom of Saudi Arabia.
Mazhor AldosaryDepartment of Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh, 11211, Kingdom of Saudi Arabia.
Rawan AlmassDepartment of Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh, 11211, Kingdom of Saudi Arabia.
Laila Al-QuaitDepartment of Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh, 11211, Kingdom of Saudi Arabia.
Wafa QubbajDepartment of Pathology and Laboratory Medicine, King Faisal Specialist Hospital and Research Centre, Riyadh, 11211, Kingdom of Saudi Arabia.
Serdar CoskunDepartment of Pathology and Laboratory Medicine, King Faisal Specialist Hospital and Research Centre, Riyadh, 11211, Kingdom of Saudi Arabia.
Khaled O AlahmadiRadiology Department, King Faisal Specialist Hospital and Research Centre, Riyadh, 11211, Kingdom of Saudi Arabia.
Muddathir H A HamadNeurology Division, Department of Pediatrics, College of Medicine, King Saud University, Riyadh, 11461, Kingdom of Saudi Arabia.
Salem AlwadaeeDepartment of Pathology and Laboratory Medicine, King Faisal Specialist Hospital and Research Centre, Riyadh, 11211, Kingdom of Saudi Arabia.
Khalid AwartaniObstetrics/Gynecology Department, King Faisal Specialist Hospital and Research Centre, Riyadh, 11211, Kingdom of Saudi Arabia.
Anas M DababoDepartment of Pathology and Laboratory Medicine, King Faisal Specialist Hospital and Research Centre, Riyadh, 11211, Kingdom of Saudi Arabia.
Futwan AlmohannaDepartment of Cell Biology, King Faisal Specialist Hospital and Research Centre, Riyadh, 11211, Kingdom of Saudi Arabia.
Dilek ColakDepartment of Biostatistics, Epidemiology and Scientific Computing, King Faisal Specialist Hospital and Research Centre, Riyadh, 11211, Kingdom of Saudi Arabia.
Mohammadreza DehghaniMedical Genetics Research Center, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.
Mohammad Yahya Vahidi MehrjardiDiabetes Research Center, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.
Murat GunelDepartment of Neurosurgery, Program On Neurogenetics, Yale School of Medicine, Yale University, New Haven, CT, USA.
A Gulhan Ercan-SencicekDepartment of Neurosurgery, Program On Neurogenetics, Yale School of Medicine, Yale University, New Haven, CT, USA.
Gouri Rao PassiDepartment of Pediatrics, Pediatric Neurology Clinic, Choithram Hospital and Research Centre, Indore, Madhya Pradesh, India.
Huma Arshad CheemaPediatric Gastroenterology Department, Children's Hospital and Institute of Child Health, Lahore, Pakistan.
Stephanie EfthymiouDepartment of Neuromuscular Disorders, UCL Queen Square Institute of Neurology, London, WC1N 3BG, UK.
Henry HouldenDepartment of Neuromuscular Disorders, UCL Queen Square Institute of Neurology, London, WC1N 3BG, UK.
Aida M Bertoli-AvellaCENTOGENE AG, Rostock, Germany.
Alice S BrooksDepartment of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam, The Netherlands.
Kyle RettererGeneDx, Gaithersburg, MD, 20877, USA.
Reza MaroofianDepartment of Neuromuscular Disorders, UCL Queen Square Institute of Neurology, London, WC1N 3BG, UK.
Namik KayaDepartment of Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh, 11211, Kingdom of Saudi Arabia.
Tjakko J van HamDepartment of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam, The Netherlands.
Tahsin Stefan BarakatDepartment of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam, The Netherlands. t.barakat@erasmusmc.nl.ORCID http://orcid.org/0000-0003-1231-1562
Erasmus MC · NLKing Faisal Specialist Hospital & Research Centre · SANational Hospital for Neurology and Neurosurgery · GBCentogene (Germany) · DEKing Saud University · SAMashhad University of Medical Sciences · IRMcMaster Children's Hospital · CAShahid Sadoughi University of Medical Sciences and Health Services · IRStanford University · USSultan Qaboos University · OMSultan Qaboos University Hospital · OMYale University · USAmsterdam Neuroscience · NLChoithram Hospital and Research Centre · INRadboud University Nijmegen · NLSt George's, University of London · GBTawam Hospital · AEUniversity of Novi Sad · RSUniversity of Sistan and Baluchestan · IR
Funding
Yale Clinical and Translational Science Award (U Component)UL1TR001863 · NCATS · YALE UNIVERSITY · PI John H. Krystal, LUCILA OHNO-MACHADO · 2016 to 2026
$102.9MYale Center for Mendelian GenomicsUM1HG006504 · NHGRI · YALE UNIVERSITY · PI GERSTEIN, MARK BENDER, GUNEL, MURAT · 2016 to 2020
$14.8MStanford Center for Undiagnosed DiseasesU01HG007708 · NHGRI · STANFORD UNIVERSITY · PI ASHLEY, EUAN A, BERNSTEIN, JONATHAN ADAM · 2014 to 2018
$8.0MWhat comes next? Engaging stakeholders in governance of participant data and relationships during the sunset of large genomic medicine research initiativesU01HG010218 · NHGRI · STANFORD UNIVERSITY · PI ASHLEY, EUAN A, BERNSTEIN, JONATHAN ADAM · 2018 to 2022
$6.3MHigh Performance Computing Instrumentation for the Yale Center for Genome AnalysiS10OD018521 · OD · YALE UNIVERSITY · PI MANE, SHRIKANT M · 2015 to 2015
$890kMedical Research Council G0601943Medical Research Council MR/S005021/1Medical Research Council MR/S01165X/1NCATS NIH HHS UL1 TR001863NHGRI NIH HHS U01 HG007708NHGRI NIH HHS U01 HG010218NHGRI NIH HHS UM1 HG006504NIH HHS S10 OD018521Wellcome TrustWellcome Trust WT093205MAWellcome Trust WT104033AIA
Abstract
Developmental and/or epileptic encephalopathies (DEEs) are a group of devastating genetic disorders, resulting in early-onset, therapy-resistant seizures and developmental delay. Here we report on 22 individuals from 15 families presenting with a severe form of intractable epilepsy, severe developmental delay, progressive microcephaly, visual disturbance and similar minor dysmorphisms. Whole exome sequencing identified a recurrent, homozygous variant (chr2:64083454A > G) in the essential UDP-glucose pyrophosphorylase (UGP2) gene in all probands. This rare variant results in a tolerable Met12Val missense change of the longer UGP2 protein isoform but causes a disruption of the start codon of the shorter isoform, which is predominant in brain. We show that the absence of the shorter isoform leads to a reduction of functional UGP2 enzyme in neural stem cells, leading to altered glycogen metabolism, upregulated unfolded protein response and premature neuronal differentiation, as modeled during pluripotent stem cell differentiation in vitro. In contrast, the complete lack of all UGP2 isoforms leads to differentiation defects in multiple lineages in human cells. Reduced expression of Ugp2a/Ugp2b in vivo in zebrafish mimics visual disturbance and mutant animals show a behavioral phenotype. Our study identifies a recurrent start codon mutation in UGP2 as a cause of a novel autosomal recessive DEE syndrome. Importantly, it also shows that isoform-specific start-loss mutations causing expression loss of a tissue-relevant isoform of an essential protein can cause a genetic disease, even when an organism-wide protein absence is incompatible with life. We provide additional examples where a similar disease mechanism applies.
Indexed as
AnimalsBrain DiseasesChild, PreschoolEpileptic SyndromesFemaleGenes, EssentialHumansInfantMaleMutationPedigreeUTP-Glucose-1-Phosphate UridylyltransferaseZebrafishUTP-Glucose-1-Phosphate UridylyltransferaseATG mutationsEpileptic encephalopathyEssential geneFounder mutationGeneticsMicrocephalyRecurrent mutationStart-loss mutationUGP2Whole exome sequencing
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