TY - JOUR T1 - 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 JF - bioRxiv DO - 10.1101/799841 SP - 799841 AU - Elena Perenthaler AU - Anita Nikoncuk AU - Soheil Yousefi AU - Woutje M. Berdowski AU - Ivan Capo AU - Herma C. van der Linde AU - Paul van den Berg AU - Edwin H. Jacobs AU - Darija Putar AU - Mehrnaz Ghazvini AU - Eleonora Aronica AU - Wilfred F.J. van IJcken AU - Walter G. de Valk AU - Evita Medici-van den Herik AU - Marjon van Slegtenhorst AU - Lauren Brick AU - Mariya Kozenko AU - Jennefer N. Kohler AU - Jonathan A. Bernstein AU - Kristin G. Monaghan AU - Amber Begtrup AU - Rebecca Torene AU - Amna Al Futaisi AU - Fathiya Al Murshedi AU - Renjith Mani AU - Faisal Al Azri AU - Erik-Jan Kamsteeg AU - Majid Mojarrad AU - Atieh Eslahi AU - Zaynab Khazaei AU - Fateme Massinaei Darmiyan AU - Mohammad Doosti AU - Ehsan Ghayoor Karimiani AU - Jana Vandrovcova AU - Faisal Zafar AU - Nuzhat Rana AU - Krishna K. Kandaswamy AU - Jozef Hertecant AU - Peter Bauer AU - Stephanie Efthymiou AU - Henry Houlden AU - Aida M. Bertoli-Avella AU - Reza Maroofian AU - Kyle Retterer AU - Alice S. Brooks AU - Tjakko J. van Ham AU - Tahsin Stefan Barakat Y1 - 2019/01/01 UR - http://biorxiv.org/content/early/2019/10/10/799841.abstract N2 - 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 12 individuals from 10 families presenting with a severe form of intractable epilepsy, severe developmental delay, progressive microcephaly and visual disturbance. 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. We show that the absence of the shorter isoform leads to a reduction of functional UGP2 enzyme in brain cell types, leading to altered glycogen metabolism, upregulated unfolded protein response and premature neuronal differentiation, as modelled 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. 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. ER -