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
Authors: Perenthaler Elena , Nikoncuk Anita , Yousefi Soheil , Berdowski Woutje M. , Alsagob Maysoon , Capo Ivan , van der Linde Herma C. , van den Berg Paul , Jacobs Edwin H. , Putar Darija , Ghazvini Mehrnaz , Aronica Eleonora , van IJcken Wilfred F. J. , de Valk Walter G. , Medici-van den Herik Evita , van Slegtenhorst Marjon , Brick Lauren , Kozenko Mariya , Kohler Jennefer N. , Bernstein Jonathan A. , Monaghan Kristin G. , Begtrup Amber , Torene Rebecca , Al Futaisi Amna , Al Murshedi Fathiya , Mani Renjith , Al Azri Faisal , Kamsteeg Erik-Jan , Mojarrad Majid , Eslahi Atieh , Khazaei Zaynab , Darmiyan Fateme Massinaei , Doosti Mohammad , Karimiani Ehsan Ghayoor , Vandrovcova Jana , Zafar Faisal , Rana Nuzhat , Kandaswamy Krishna K. , Hertecant Jozef , Bauer Peter , AlMuhaizea Mohammed A. , Salih Mustafa A. , Aldosary Mazhor , Almass Rawan , Al-Quait Laila , Qubbaj Wafa , Coskun Serdar , Alahmadi Khaled O. , Hamad Muddathir H. A. , Alwadaee Salem , Awartani Khalid , Dababo Anas M. , Almohanna Futwan , Colak Dilek , Dehghani Mohammadreza , Mehrjardi Mohammad Yahya Vahidi , Gunel Murat , Ercan-Sencicek A. Gulhan , Passi Gouri Rao , Cheema Huma Arshad , Efthymiou Stephanie , Houlden Henry , Bertoli-Avella Aida M. , Brooks Alice S. , Retterer Kyle , Maroofian Reza , Kaya Namik , van Ham Tjakko J. , Barakat Tahsin Stefan 
Published: December 2019

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 essentialUDP-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 inUGP2as 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.