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. BernsteinKristin 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*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

32 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)415-442
Number of pages28
JournalActa Neuropathologica
Issue number3
Publication statusPublished - Mar 1 2020


  • ATG mutations
  • Epileptic encephalopathy
  • Essential gene
  • Founder mutation
  • Genetics
  • Microcephaly
  • Recurrent mutation
  • Start-loss mutation
  • UGP2
  • Whole exome sequencing

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

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