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

Perenthaler, E. and Nikoncuk, A. and Yousefi, S. and Berdowski, W. M. and Alsagob, M. and Capo, I. and van der Linde, H. C. and van den Berg, P. and Jacobs, E. H. and Putar, D. and Ghazvini, M. and Aronica, E. and van Ijcken, W. F. J. and de Valk, W. G. and Medici-van den Herik, E. and van Slegtenhorst, M. and Brick, L. and Kozenko, M. and Kohler, J. N. and Bernstein, J. A. and Monaghan, K. G. and Begtrup, A. and Torene, R. and Al Futaisi, A. and Al Murshedi, F. and Mani, R. and Al Azri, F. and Kamsteeg, E. J. and Mojarrad, M. and Eslahi, A. and Khazaei, Z. and Darmiyan, F. M. and Doosti, M. and Karimiani, E. G. and Vandrovcova, J. and Zafar, F. and Rana, N. and Kandaswamy, K. K. and Hertecant, J. and Bauer, P. and AlMuhaizea, M. A. and Salih, M. A. and Aldosary, M. and Almass, R. and Al-Quait, L. and Qubbaj, W. and Coskun, S. and Alahmadi, K. O. and Hamad, M. H. A. and Alwadaee, S. and Awartani, K. and Dababo, A. M. and Almohanna, F. and Colak, D. and Dehghani, M. and Mehrjardi, M. Y. V. and Gunel, M. and Ercan-Sencicek, A. G. and Passi, G. R. and Cheema, H. A. and Efthymiou, S. and Houlden, H. and Bertoli-Avella, A. M. and Brooks, A. S. and Retterer, K. and Maroofian, R. and Kaya, N. and van Ham, T. J. and Barakat, T. S. (2019) 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. Acta Neuropathologica.

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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.pdf

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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. © 2019, The Author(s).

Item Type: Article
Additional Information: Export Date: 16 February 2020 CODEN: ANPTA Correspondence Address: Barakat, T.S.; Department of Clinical Genetics, Erasmus MC University Medical CenterNetherlands; email: t.barakat@erasmusmc.nl
Uncontrolled Keywords: ATG mutations Epileptic encephalopathy Essential gene Founder mutation Genetics Microcephaly Recurrent mutation Start-loss mutation UGP2 Whole exome sequencing
Subjects: WL Nervous system
Divisions: Mashhad University of Medical Sciences
Depositing User: mr lib1 lib1
Date Deposited: 21 Jun 2020 09:31
Last Modified: 21 Jun 2020 09:31
URI: http://eprints.mums.ac.ir/id/eprint/18586

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