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Pregled bibliografske jedinice broj: 1088039

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

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 et al.
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 (2020), 3; 415-442 doi:10.1007/s00401-019-02109-6 (međunarodna recenzija, članak, znanstveni)

CROSBI ID: 1088039 Za ispravke kontaktirajte CROSBI podršku putem web obrasca

Naslov
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

Autori
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

Izvornik
Acta neuropathologica (0001-6322) 139 (2020), 3; 415-442

Vrsta, podvrsta i kategorija rada
Radovi u časopisima, članak, znanstveni

Ključne riječi
epileptic encephalopathy ; UGP2 ; ATG mutations ; start-loss mutation ; genetics ; whole exome sequencing ; microcephaly ; recurrent mutation ; founder mutation ; essential gene

Sažetak
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.

Izvorni jezik
Engleski

Znanstvena područja
Biologija, Temeljne medicinske znanosti, Biotehnologija u biomedicini (prirodno područje, biomedicina i zdravstvo, biotehničko područje)



POVEZANOST RADA

Profili:

Avatar Url Darija Putar Brajković (autor)

Poveznice na cjeloviti tekst rada:

doi link.springer.com

Citiraj ovu publikaciju:

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 et al.
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 (2020), 3; 415-442 doi:10.1007/s00401-019-02109-6 (međunarodna recenzija, članak, znanstveni)
Perenthaler, E., Nikoncuk, A., Yousefi, S., Berdowski, W., Alsagob, M., Capo, I., van der Linde, H., van den Berg, P., Jacobs, E. & Putar, D. (2020) 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 doi:10.1007/s00401-019-02109-6.
@article{article, author = {Perenthaler, Elena and Nikoncuk, Anita and Yousefi, Soheil and Berdowski, Woutje M. and Alsagob, Maysoon and Capo, Ivan and van der Linde, Herma C. and van den Berg, Paul and Jacobs, Edwin H. and Putar, Darija and Ghazvini, Mehrnaz and Aronica, Eleonora and van IJcken, Wilfred F. J. and de Valk, Walter G. and Medici-van den Herik, Evita and van Slegtenhorst, Marjon and Brick, Lauren and Kozenko, Mariya and Kohler, Jennefer N. and Bernstein, Jonathan A. and Monaghan, Kristin G. and Begtrup, Amber and Torene, Rebecca and Al Futaisi, Amna and Al Murshedi, Fathiya and Mani, Renjith and Al Azri, Faisal and Kamsteeg, Erik-Jan and Mojarrad, Majid and Eslahi, Atieh and Khazaei, Zaynab and Darmiyan, Fateme Massinaei and Doosti, Mohammad and Karimiani, Ehsan Ghayoor and Vandrovcova, Jana and Zafar, Faisal and Rana, Nuzhat and Kandaswamy, Krishna K. and Hertecant, Jozef and Bauer, Peter and AlMuhaizea, Mohammed A. and Salih, Mustafa A. and Aldosary, Mazhor and Almass, Rawan and Al-Quait, Laila and Qubbaj, Wafa and Coskun, Serdar and Alahmadi, Khaled O. and Hamad, Muddathir H. A. and Alwadaee, Salem and Awartani, Khalid and Dababo, Anas M. and Almohanna, Futwan and Colak, Dilek and Dehghani, Mohammadreza and Mehrjardi, Mohammad Yahya Vahidi and Gunel, Murat and Ercan-Sencicek, A. Gulhan and Passi, Gouri Rao and Cheema, Huma Arshad and Efthymiou, Stephanie and Houlden, Henry and Bertoli-Avella, Aida M. and Brooks, Alice S. and Retterer, Kyle and Maroofian, Reza and Kaya, Namik and van Ham, Tjakko J. and Barakat, Tahsin Stefan}, year = {2020}, pages = {415-442}, DOI = {10.1007/s00401-019-02109-6}, keywords = {epileptic encephalopathy, UGP2, ATG mutations, start-loss mutation, genetics, whole exome sequencing, microcephaly, recurrent mutation, founder mutation, essential gene}, journal = {Acta neuropathologica}, doi = {10.1007/s00401-019-02109-6}, volume = {139}, number = {3}, issn = {0001-6322}, title = {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}, keyword = {epileptic encephalopathy, UGP2, ATG mutations, start-loss mutation, genetics, whole exome sequencing, microcephaly, recurrent mutation, founder mutation, essential gene} }
@article{article, author = {Perenthaler, Elena and Nikoncuk, Anita and Yousefi, Soheil and Berdowski, Woutje M. and Alsagob, Maysoon and Capo, Ivan and van der Linde, Herma C. and van den Berg, Paul and Jacobs, Edwin H. and Putar, Darija and Ghazvini, Mehrnaz and Aronica, Eleonora and van IJcken, Wilfred F. J. and de Valk, Walter G. and Medici-van den Herik, Evita and van Slegtenhorst, Marjon and Brick, Lauren and Kozenko, Mariya and Kohler, Jennefer N. and Bernstein, Jonathan A. and Monaghan, Kristin G. and Begtrup, Amber and Torene, Rebecca and Al Futaisi, Amna and Al Murshedi, Fathiya and Mani, Renjith and Al Azri, Faisal and Kamsteeg, Erik-Jan and Mojarrad, Majid and Eslahi, Atieh and Khazaei, Zaynab and Darmiyan, Fateme Massinaei and Doosti, Mohammad and Karimiani, Ehsan Ghayoor and Vandrovcova, Jana and Zafar, Faisal and Rana, Nuzhat and Kandaswamy, Krishna K. and Hertecant, Jozef and Bauer, Peter and AlMuhaizea, Mohammed A. and Salih, Mustafa A. and Aldosary, Mazhor and Almass, Rawan and Al-Quait, Laila and Qubbaj, Wafa and Coskun, Serdar and Alahmadi, Khaled O. and Hamad, Muddathir H. A. and Alwadaee, Salem and Awartani, Khalid and Dababo, Anas M. and Almohanna, Futwan and Colak, Dilek and Dehghani, Mohammadreza and Mehrjardi, Mohammad Yahya Vahidi and Gunel, Murat and Ercan-Sencicek, A. Gulhan and Passi, Gouri Rao and Cheema, Huma Arshad and Efthymiou, Stephanie and Houlden, Henry and Bertoli-Avella, Aida M. and Brooks, Alice S. and Retterer, Kyle and Maroofian, Reza and Kaya, Namik and van Ham, Tjakko J. and Barakat, Tahsin Stefan}, year = {2020}, pages = {415-442}, DOI = {10.1007/s00401-019-02109-6}, keywords = {epileptic encephalopathy, UGP2, ATG mutations, start-loss mutation, genetics, whole exome sequencing, microcephaly, recurrent mutation, founder mutation, essential gene}, journal = {Acta neuropathologica}, doi = {10.1007/s00401-019-02109-6}, volume = {139}, number = {3}, issn = {0001-6322}, title = {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}, keyword = {epileptic encephalopathy, UGP2, ATG mutations, start-loss mutation, genetics, whole exome sequencing, microcephaly, recurrent mutation, founder mutation, essential gene} }

Časopis indeksira:


  • Current Contents Connect (CCC)
  • Web of Science Core Collection (WoSCC)
    • Science Citation Index Expanded (SCI-EXP)
    • SCI-EXP, SSCI i/ili A&HCI
  • Scopus
  • MEDLINE

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