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

Elena Perenthaler; Anita Nikoncuk; Soheil Yousefi; Woutje M Berdowski; Maysoon Alsagob; Ivan Capo; Herma C van der Linde; Paul van den Berg; Edwin H Jacobs; Darija Putar; Mehrnaz Ghazvini; Eleonora Aronica; Wilfred F J van IJcken; Walter G de Valk; Evita Medici-van den Herik; Marjon van Slegtenhorst; Lauren Brick; Mariya Kozenko; Jennefer N Kohler; Jonathan A Bernstein; Kristin G Monaghan; Amber Begtrup; Rebecca Torene; Amna Al Futaisi; Fathiya Al Murshedi; Renjith Mani; Faisal Al Azri; Erik-Jan Kamsteeg; Majid Mojarrad; Atieh Eslahi; Zaynab Khazaei; Fateme Massinaei Darmiyan; Mohammad Doosti; Ehsan Ghayoor Karimiani; Jana Vandrovcova; Faisal Zafar; Nuzhat Rana; Krishna K Kandaswamy; Jozef Hertecant; Peter Bauer; Mohammed A AlMuhaizea; Mustafa A Salih; Mazhor Aldosary; Rawan Almass; Laila Al-Quait; Wafa Qubbaj; Serdar Coskun; Khaled O Alahmadi; Muddathir H A Hamad; Salem Alwadaee; Khalid Awartani; Anas M Dababo; Futwan Almohanna; Dilek Colak; Mohammadreza Dehghani; Mohammad Yahya Vahidi Mehrjardi; Murat Gunel; A Gulhan Ercan-Sencicek; Gouri Rao Passi; Huma Arshad Cheema; Stephanie Efthymiou; Henry Houlden; Aida M Bertoli-Avella; Alice S Brooks; Kyle Retterer; Reza Maroofian; Namik Kaya; Tjakko J van Ham; Tahsin Stefan Barakat

doi:10.1007/s00401-019-02109-6

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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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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

Elena Perenthaler, Anita Nikoncuk, Soheil Yousefi, Woutje M Berdowski, Maysoon Alsagob, Ivan Capo, Herma C van der Linde, Paul van den Berg, Edwin H Jacobs, Darija Putar, …

Acta neuropathologica, Vol.139(3), pp.415-442

01/03/2020

DOI: https://doi.org/10.1007/s00401-019-02109-6

PMCID: PMC7035241

PMID: 31820119

Abstract

Animals

Brain Diseases - genetics

Child, Preschool

Epileptic Syndromes - genetics

Female

Genes, Essential - genetics

Humans

Infant

Male

Mutation

Pedigree

UTP-Glucose-1-Phosphate Uridylyltransferase - genetics

Zebrafish

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.

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Title: 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
Creators - without role: Elena Perenthaler - Erasmus MC
Anita Nikoncuk - Erasmus MC
Soheil Yousefi - Erasmus MC
Woutje M Berdowski - Erasmus MC
Maysoon Alsagob - King Faisal Specialist Hospital & Research Centre
Ivan Capo - University of Novi Sad
Herma C van der Linde - Erasmus MC
Paul van den Berg - Erasmus MC
Edwin H Jacobs - Erasmus MC
Darija Putar - Erasmus MC
Mehrnaz Ghazvini - Erasmus MC
Eleonora Aronica - Amsterdam Neuroscience
Wilfred F J van IJcken - Erasmus MC
Walter G de Valk - Erasmus MC
Evita Medici-van den Herik - Department of Neurology, Erasmus MC University Medical Center, Rotterdam, The Netherlands
Marjon van Slegtenhorst - Erasmus MC
Lauren Brick - McMaster Children's Hospital
Mariya Kozenko - McMaster Children's Hospital
Jennefer N Kohler - Stanford University
Jonathan A Bernstein - Stanford University
Kristin G Monaghan - GeneDx, Gaithersburg, USA
Amber Begtrup - GeneDx, Gaithersburg, USA
Rebecca Torene - GeneDx, Gaithersburg, USA
Amna Al Futaisi - Sultan Qaboos University
Fathiya Al Murshedi - Sultan Qaboos University Hospital
Renjith Mani - Sultan Qaboos University
Faisal Al Azri - Sultan Qaboos University Hospital
Erik-Jan Kamsteeg - Radboud University Medical Center
Majid Mojarrad - Mashhad University of Medical Sciences
Atieh Eslahi - Mashhad University of Medical Sciences
Zaynab Khazaei - Genetic Center of Khorasan Razavi, Mashhad, Iran
Fateme Massinaei Darmiyan - University of Sistan and Baluchestan
Mohammad Doosti - Department Medical Genetics, Next Generation Genetic Polyclinic, Mashhad, Iran
Ehsan Ghayoor Karimiani - St George's, University of London
Jana Vandrovcova - National Hospital for Neurology and Neurosurgery
Faisal Zafar - Department of Paediatric Neurology, Children’s Hospital and Institute of Child Health, Multan, Pakistan
Nuzhat Rana - Department of Paediatric Neurology, Children’s Hospital and Institute of Child Health, Multan, Pakistan
Krishna K Kandaswamy - Centogene
Jozef Hertecant - Tawam Hospital
Peter Bauer - Centogene
Mohammed A AlMuhaizea - King Faisal Specialist Hospital & Research Centre
Mustafa A Salih - King Saud University
Mazhor Aldosary - Department of Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh, 11211, Kingdom of Saudi Arabia
Rawan Almass - King Faisal Specialist Hospital & Research Centre
Laila Al-Quait - Department of Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh, 11211, Kingdom of Saudi Arabia
Wafa Qubbaj - King Faisal Specialist Hospital & Research Centre
Serdar Coskun - King Faisal Specialist Hospital & Research Centre
Khaled O Alahmadi - King Faisal Specialist Hospital & Research Centre
Muddathir H A Hamad - King Saud University
Salem Alwadaee - King Faisal Specialist Hospital & Research Centre
Khalid Awartani - King Faisal Specialist Hospital & Research Centre
Anas M Dababo - King Faisal Specialist Hospital & Research Centre
Futwan Almohanna - Department of Cell Biology, King Faisal Specialist Hospital and Research Centre, Riyadh, 11211, Kingdom of Saudi Arabia
Dilek Colak - King Faisal Specialist Hospital & Research Centre
Mohammadreza Dehghani - Shahid Sadoughi University of Medical Sciences and Health Services
Mohammad Yahya Vahidi Mehrjardi - Shahid Sadoughi University of Medical Sciences and Health Services
Murat Gunel - Yale University
A Gulhan Ercan-Sencicek - Yale University
Gouri Rao Passi - Choithram Hospital and Research Centre
Huma Arshad Cheema - Pediatric Gastroenterology Department, Children’s Hospital and Institute of Child Health, Lahore, Pakistan
Stephanie Efthymiou - National Hospital for Neurology and Neurosurgery
Henry Houlden - National Hospital for Neurology and Neurosurgery
Aida M Bertoli-Avella - Centogene
Alice S Brooks - Erasmus MC
Kyle Retterer - GeneDx, Gaithersburg, USA
Reza Maroofian - National Hospital for Neurology and Neurosurgery
Namik Kaya - King Faisal Specialist Hospital & Research Centre
Tjakko J van Ham - Erasmus MC
Tahsin Stefan Barakat - Erasmus MC
Publication Details: Acta neuropathologica, Vol.139(3), pp.415-442
Grant note: G0601943 / Medical Research Council MR/S005021/1 / Medical Research Council WT104033AIA / Wellcome Trust U01 HG007708 / NHGRI NIH HHS UL1 TR001863 / NCATS NIH HHS S10 OD018521 / NIH HHS WT093205MA / Wellcome Trust MR/S01165X/1 / Medical Research Council U01 HG010218 / NHGRI NIH HHS
Identifiers: 9913493608331
Academic Unit: King Faisal University; Alfaisal University; King Saud University
Language: English
Resource Type: Journal article