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

• DOI: 10.1007/s00401-019-02109-6
• Publication Date: 2019-12-09T19:04:13Z
• Authors: Elena Perenthaler; Anita Nikoncuk; Soheil Yousefi; Woutje M. Berdowski; Maysoon Alsagob; Ivan Capo; Herma C. van der ...; Paul van den Berg; Edwin H. Jacobs; Darija Putar; Mehrnaz Ghazvini; Eleonora Aronica; Wilfred F. J. van...; Walter G. de Valk; Evita Medici-van ...; Marjon van Slegte...; Lauren Brick; Mariya Kozenko; Jennefer N. Kohler; Jonathan A. Berns...; 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 ...; Mohammad Doosti; Ehsan Ghayoor Kar...; Jana Vandrovcova; Faisal Zafar; Nuzhat Rana; Krishna K. Kandas...; Jozef Hertecant; Peter Bauer; Mohammed A. AlMuh...; Mustafa A. Salih; Mazhor Aldosary; Rawan Almass; Laila Al-Quait; Wafa Qubbaj; Serdar Coskun; Khaled O. Alahmadi; Muddathir H. A. H...; Salem Alwadaee; Khalid Awartani; Anas M. Dababo; Futwan Almohanna; Dilek Colak; Mohammadreza Dehg...; Mohammad Yahya Va...; Murat Gunel; A. Gulhan Ercan-S...; Gouri Rao Passi; Huma Arshad Cheema; Stephanie Efthymiou; Henry Houlden; Aida M. Bertoli-A...; Alice S. Brooks; Kyle Retterer; Reza Maroofian; Namik Kaya; Tjakko J. van Ham; Tahsin Stefan Bar...
• Keywords: Microcephaly; Protein isoform

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 severe form intractable epilepsy, delay, progressive microcephaly, visual disturbance similar minor dysmorphisms. Whole exome sequencing identified recurrent, homozygous variant (chr2:64083454A > G) the essential UDP-glucose pyrophosphorylase (UGP2) gene all probands. This rare results tolerable Met12Val missense change longer UGP2 protein isoform but causes disruption start codon shorter isoform, which is predominant brain. We show that absence leads to reduction functional enzyme neural stem cells, leading altered glycogen metabolism, upregulated unfolded response premature neuronal differentiation, as modeled during pluripotent cell differentiation vitro. In contrast, complete lack isoforms defects multiple lineages human cells. Reduced expression Ugp2a/Ugp2b vivo zebrafish mimics mutant animals behavioral phenotype. Our study identifies recurrent mutation cause novel autosomal recessive DEE syndrome. Importantly, it also shows isoform-specific start-loss mutations causing loss tissue-relevant an can disease, even when organism-wide incompatible life. provide additional examples where disease mechanism applies.