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.

Autor: Perenthaler E; Department of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam, The Netherlands., Nikoncuk A; Department of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam, The Netherlands., Yousefi S; Department of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam, The Netherlands., Berdowski WM; Department of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam, The Netherlands., Alsagob M; Department of Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh, 11211, Kingdom of Saudi Arabia., Capo I; Department for Histology and Embryology, Faculty of Medicine Novi Sad, University of Novi Sad, Novi Sad, Serbia., van der Linde HC; Department of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam, The Netherlands., van den Berg P; Department of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam, The Netherlands., Jacobs EH; Department of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam, The Netherlands., Putar D; Department of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam, The Netherlands., Ghazvini M; iPS Cell Core Facility, Erasmus MC University Medical Center, Rotterdam, The Netherlands., Aronica E; Department of (Neuro)Pathology, Amsterdam Neuroscience, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.; Stichting Epilepsie Instellingen Nederland (SEIN), Zwolle, The Netherlands., van IJcken WFJ; Center for Biomics, Department of Cell Biology, Erasmus MC University Medical Center, Rotterdam, The Netherlands., de Valk WG; Department of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam, The Netherlands., Medici-van den Herik E; Department of Neurology, Erasmus MC University Medical Center, Rotterdam, The Netherlands., van Slegtenhorst M; Department of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam, The Netherlands., Brick L; Division of Genetics, McMaster Children's Hospital, Hamilton, ON, L8S 4J9, Canada., Kozenko M; Division of Genetics, McMaster Children's Hospital, Hamilton, ON, L8S 4J9, Canada., Kohler JN; Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA, 94035, USA., Bernstein JA; Division of Medical Genetics, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, 94035, USA., Monaghan KG; GeneDx, Gaithersburg, MD, 20877, USA., Begtrup A; GeneDx, Gaithersburg, MD, 20877, USA., Torene R; GeneDx, Gaithersburg, MD, 20877, USA., Al Futaisi A; Department of Child Health, College of Medicine and Health Sciences, Sultan Qaboos University, Muscat, Oman., Al Murshedi F; Genetic and Developmental Medicine Clinic, Sultan Qaboos University Hospital, Muscat, Oman., Mani R; Department of Child Health, College of Medicine and Health Sciences, Sultan Qaboos University, Muscat, Oman., Al Azri F; Department of Radiology and Molecular Imaging, Sultan Qaboos University Hospital, Muscat, Oman., Kamsteeg EJ; Department of Human Genetics, Radboud University Medical Centre, Nijmegen, The Netherlands., Mojarrad M; Department of Medical Genetics, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.; Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.; Genetic Center of Khorasan Razavi, Mashhad, Iran., Eslahi A; Department of Medical Genetics, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.; Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran., Khazaei Z; Genetic Center of Khorasan Razavi, Mashhad, Iran., Darmiyan FM; Genetic Counseling Center, Welfare Organization of Sistan and Baluchestan, Zahedan, Iran., Doosti M; Department Medical Genetics, Next Generation Genetic Polyclinic, Mashhad, Iran., Karimiani EG; Molecular and Clinical Sciences Institute, St. George's University of London, Cranmer Terrace, London, SW17 0RE, UK.; Innovative Medical Research Center, Mashhad Branch, Islamic Azad University, Mashhad, Iran., Vandrovcova J; Department of Neuromuscular Disorders, UCL Queen Square Institute of Neurology, London, WC1N 3BG, UK., Zafar F; Department of Paediatric Neurology, Children's Hospital and Institute of Child Health, Multan, 60000, Pakistan., Rana N; Department of Paediatric Neurology, Children's Hospital and Institute of Child Health, Multan, 60000, Pakistan., Kandaswamy KK; CENTOGENE AG, Rostock, Germany., Hertecant J; Department of Pediatrics, Tawam Hospital, and College of Medicine and Health Sciences, UAE University, Al-Ain, UAE., Bauer P; CENTOGENE AG, Rostock, Germany., AlMuhaizea MA; Department of Neurosciences, King Faisal Specialist Hospital and Research Centre, Riyadh, 11211, Kingdom of Saudi Arabia., Salih MA; Neurology Division, Department of Pediatrics, College of Medicine, King Saud University, Riyadh, 11461, Kingdom of Saudi Arabia., Aldosary M; Department of Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh, 11211, Kingdom of Saudi Arabia., Almass R; Department of Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh, 11211, Kingdom of Saudi Arabia., Al-Quait L; Department of Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh, 11211, Kingdom of Saudi Arabia., Qubbaj W; Department of Pathology and Laboratory Medicine, King Faisal Specialist Hospital and Research Centre, Riyadh, 11211, Kingdom of Saudi Arabia., Coskun S; Department of Pathology and Laboratory Medicine, King Faisal Specialist Hospital and Research Centre, Riyadh, 11211, Kingdom of Saudi Arabia., Alahmadi KO; Radiology Department, King Faisal Specialist Hospital and Research Centre, Riyadh, 11211, Kingdom of Saudi Arabia., Hamad MHA; Neurology Division, Department of Pediatrics, College of Medicine, King Saud University, Riyadh, 11461, Kingdom of Saudi Arabia., Alwadaee S; Department of Pathology and Laboratory Medicine, King Faisal Specialist Hospital and Research Centre, Riyadh, 11211, Kingdom of Saudi Arabia., Awartani K; Obstetrics/Gynecology Department, King Faisal Specialist Hospital and Research Centre, Riyadh, 11211, Kingdom of Saudi Arabia., Dababo AM; Department of Pathology and Laboratory Medicine, King Faisal Specialist Hospital and Research Centre, Riyadh, 11211, Kingdom of Saudi Arabia., Almohanna F; Department of Cell Biology, King Faisal Specialist Hospital and Research Centre, Riyadh, 11211, Kingdom of Saudi Arabia., Colak D; Department of Biostatistics, Epidemiology and Scientific Computing, King Faisal Specialist Hospital and Research Centre, Riyadh, 11211, Kingdom of Saudi Arabia., Dehghani M; Medical Genetics Research Center, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.; Yazd Reproductive Sciences Institute, Shahid Sadoughi University of Medical Sciences, Yazd, Iran., Mehrjardi MYV; Diabetes Research Center, Shahid Sadoughi University of Medical Sciences, Yazd, Iran., Gunel M; Department of Neurosurgery, Program On Neurogenetics, Yale School of Medicine, Yale University, New Haven, CT, USA., Ercan-Sencicek AG; Department of Neurosurgery, Program On Neurogenetics, Yale School of Medicine, Yale University, New Haven, CT, USA.; Masonic Medical Research Institute, Utica, NY, USA., Passi GR; Department of Pediatrics, Pediatric Neurology Clinic, Choithram Hospital and Research Centre, Indore, Madhya Pradesh, India., Cheema HA; Pediatric Gastroenterology Department, Children's Hospital and Institute of Child Health, Lahore, Pakistan., Efthymiou S; Department of Neuromuscular Disorders, UCL Queen Square Institute of Neurology, London, WC1N 3BG, UK., Houlden H; Department of Neuromuscular Disorders, UCL Queen Square Institute of Neurology, London, WC1N 3BG, UK., Bertoli-Avella AM; CENTOGENE AG, Rostock, Germany., Brooks AS; Department of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam, The Netherlands., Retterer K; GeneDx, Gaithersburg, MD, 20877, USA., Maroofian R; Department of Neuromuscular Disorders, UCL Queen Square Institute of Neurology, London, WC1N 3BG, UK., Kaya N; Department of Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh, 11211, Kingdom of Saudi Arabia., van Ham TJ; Department of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam, The Netherlands., Barakat TS; Department of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam, The Netherlands. t.barakat@erasmusmc.nl.
Jazyk: angličtina
Zdroj: Acta neuropathologica [Acta Neuropathol] 2020 Mar; Vol. 139 (3), pp. 415-442. Date of Electronic Publication: 2019 Dec 09.
DOI: 10.1007/s00401-019-02109-6
Abstrakt: 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.
Databáze: MEDLINE
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