PUBLICATION

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, E., Nikoncuk, A., Yousefi, S., Berdowski, W.M., Alsagob, M., Capo, I., van der Linde, H.C., van den Berg, P., Jacobs, E.H., Putar, D., Ghazvini, M., Aronica, E., van IJcken, W.F.J., de Valk, W.G., Medici-van den Herik, E., van Slegtenhorst, M., Brick, L., Kozenko, M., Kohler, J.N., Bernstein, J.A., Monaghan, K.G., Begtrup, A., Torene, R., Al Futaisi, A., Al Murshedi, F., Mani, R., Al Azri, F., Kamsteeg, E.J., Mojarrad, M., Eslahi, A., Khazaei, Z., Darmiyan, F.M., Doosti, M., Karimiani, E.G., Vandrovcova, J., Zafar, F., Rana, N., Kandaswamy, K.K., Hertecant, J., Bauer, P., AlMuhaizea, M.A., Salih, M.A., Aldosary, M., Almass, R., Al-Quait, L., Qubbaj, W., Coskun, S., Alahmadi, K.O., Hamad, M.H.A., Alwadaee, S., Awartani, K., Dababo, A.M., Almohanna, F., Colak, D., Dehghani, M., Mehrjardi, M.Y.V., Gunel, M., Ercan-Sencicek, A.G., Passi, G.R., Cheema, H.A., Efthymiou, S., Houlden, H., Bertoli-Avella, A.M., Brooks, A.S., Retterer, K., Maroofian, R., Kaya, N., van Ham, T.J., Barakat, T.S.
ID
ZDB-PUB-191212-25
Date
2019
Source
Acta Neuropathologica   139(3): 415-442 (Journal)
Registered Authors
van der Linde, Herma
Keywords
ATG mutations, Epileptic encephalopathy, Essential gene, Founder mutation, Genetics, Microcephaly, Recurrent mutation, Start-loss mutation, UGP2, Whole exome sequencing
MeSH Terms
  • Animals
  • Brain Diseases/genetics*
  • Child, Preschool
  • Epileptic Syndromes/genetics*
  • Female
  • Genes, Essential/genetics*
  • Humans
  • Infant
  • Male
  • Mutation
  • Pedigree
  • UTP-Glucose-1-Phosphate Uridylyltransferase/genetics*
  • Zebrafish
PubMed
31820119 Full text @ Acta Neuropathol.
Citation
Perenthaler, E., Nikoncuk, A., Yousefi, S., Berdowski, W.M., Alsagob, M., Capo, I., van der Linde, H.C., van den Berg, P., Jacobs, E.H., Putar, D., Ghazvini, M., Aronica, E., van IJcken, W.F.J., de Valk, W.G., Medici-van den Herik, E., van Slegtenhorst, M., Brick, L., Kozenko, M., Kohler, J.N., Bernstein, J.A., Monaghan, K.G., Begtrup, A., Torene, R., Al Futaisi, A., Al Murshedi, F., Mani, R., Al Azri, F., Kamsteeg, E.J., Mojarrad, M., Eslahi, A., Khazaei, Z., Darmiyan, F.M., Doosti, M., Karimiani, E.G., Vandrovcova, J., Zafar, F., Rana, N., Kandaswamy, K.K., Hertecant, J., Bauer, P., AlMuhaizea, M.A., Salih, M.A., Aldosary, M., Almass, R., Al-Quait, L., Qubbaj, W., Coskun, S., Alahmadi, K.O., Hamad, M.H.A., Alwadaee, S., Awartani, K., Dababo, A.M., Almohanna, F., Colak, D., Dehghani, M., Mehrjardi, M.Y.V., Gunel, M., Ercan-Sencicek, A.G., Passi, G.R., Cheema, H.A., Efthymiou, S., Houlden, H., Bertoli-Avella, A.M., Brooks, A.S., Retterer, K., Maroofian, R., Kaya, N., van Ham, T.J., 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. 139(3):415-442.
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.
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Human Disease / Model
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Engineered Foreign Genes
Mapping
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