The homologous genes GTPBP1 and GTPBP2 encode GTP-binding proteins 1 and 2, which are involved in ribosomal homeostasis. Pathogenic variants in GTPBP2 were recently shown to be an ultra-rare cause of neurodegenerative or neurodevelopmental disorders (NDDs). Until now, no human phenotype has been linked to GTPBP1. Here, we describe individuals carrying bi-allelic GTPBP1 variants that display an identical phenotype with GTPBP2 and characterize the overall spectrum of GTP-binding protein (1/2)-related disorders. In this study, 20 individuals from 16 families with distinct NDDs and syndromic facial features were investigated by whole-exome (WES) or whole-genome (WGS) sequencing. To assess the functional impact of the identified genetic variants, semi-quantitative PCR, western blot, and ribosome profiling assays were performed in fibroblasts from affected individuals. We also investigated the effect of reducing expression of CG2017, an ortholog of human GTPBP1/2, in the fruit fly Drosophila melanogaster. Individuals with bi-allelic GTPBP1 or GTPBP2 variants presented with microcephaly, profound neurodevelopmental impairment, pathognomonic craniofacial features, and ectodermal defects. Abnormal vision and/or hearing, progressive spasticity, choreoathetoid movements, refractory epilepsy, and brain atrophy were part of the core phenotype of this syndrome. Cell line studies identified a loss-of-function (LoF) impact of the disease-associated variants but no significant abnormalities on ribosome profiling. Reduced expression of CG2017 isoforms was associated with locomotor impairment in Drosophila. In conclusion, bi-allelic GTPBP1 and GTPBP2 LoF variants cause an identical, distinct neurodevelopmental syndrome. Mutant CG2017 knockout flies display motor impairment, highlighting the conserved role for GTP-binding proteins in CNS development across species.
Bi-allelic genetic variants in the translational GTPases GTPBP1 and GTPBP2 cause a distinct identical neurodevelopmental syndrome / Salpietro, V.; Maroofian, R.; Zaki, M. S.; Wangen, J.; Ciolfi, A.; Barresi, S.; Efthymiou, S.; Lamaze, A.; Aughey, G. N.; Al Mutairi, F.; Rad, A.; Rocca, C.; Cali, E.; Accogli, A.; Zara, F.; Striano, P.; Mojarrad, M.; Tariq, H.; Giacopuzzi, E.; Taylor, J. C.; Oprea, G.; Skrahina, V.; Rehman, K. U.; Abd Elmaksoud, M.; Bassiony, M.; El Said, H. G.; Abdel-Hamid, M. S.; Al Shalan, M.; Seo, G.; Kim, S.; Lee, H.; Khang, R.; Issa, M. Y.; Elbendary, H. M.; Rafat, K.; Marinakis, N. M.; Traeger-Synodinos, J.; Ververi, A.; Sourmpi, M.; Eslahi, A.; Khadivi Zand, F.; Beiraghi Toosi, M.; Babaei, M.; Jackson, A.; Hannah, M. G.; Bugiardini, E.; Bertini, E.; Kriouile, Y.; El-Khorassani, M.; Aguennouz, M.; Groppa, S.; Karashova, B. M.; Goraya, J. S.; Sultan, T.; Avdjieva, D.; Kathom, H.; Tincheva, R.; Banu, S.; Veggiotti, P.; Verrotti, A.; Lanari, M.; Savasta, S.; Macaya, A.; Garavaglia, B.; Borgione, E.; Papacostas, S.; Vikelis, M.; Chelban, V.; Kaiyrzhanov, R.; Cortese, A.; Sullivan, R.; Papanicolaou, E. Z.; Dardiotis, E.; Maqbool, S.; Ibrahim, S.; Kirmani, S.; Rana, N. N.; Atawneh, O.; Lim, S. -Y.; Zuccotti, G. V.; Marseglia, G. L.; Esposito, S.; Shaikh, F.; Cogo, P.; Corsello, G.; Mangano, S.; Nardello, R.; Mangano, D.; Scardamaglia, A.; Koutsis, G.; Scuderi, C.; Ferrara, P.; Morello, G.; Zollo, M.; Berni-Canani, R.; Terracciano, L. M.; Sisto, A.; Di Fabio, S.; Strano, F.; Scorrano, G.; Di Bella, S.; Di Francesco, L.; Manizha, G.; Isrofilov, M.; Guliyeva, U.; Salayev, K.; Khachatryan, S.; Xiromerisiou, G.; Spanaki, C.; Fiorillo, C.; Iacomino, M.; Gaudio, E.; Munell, F.; Gagliano, A.; Jan, F.; Chimenz, R.; Gitto, E.; Iughetti, L.; Di Rosa, G.; Maghnie, M.; Pettoello-Mantovani, M.; Gupta, N.; Kabra, M.; Benrhouma, H.; Tazir, M.; Bottone, G.; Farello, G.; Delvecchio, M.; Di-Donato, G.; Obeid, M.; Bakhtadze, S.; Saadi, N. W.; Miraglia-Del-Giudice, M.; Maccarone, R.; Triki, C. C.; Kara, M.; Karimiani, E. G.; Salih, A. M.; Ramenghi, L. A.; Seri, M.; Di-Falco, G.; Mandara, L.; Barrano, G.; Elisa, M.; Cherubini, E.; Operto, F. F.; Valenzise, M.; Cattaneo, A.; Zazzeroni, F.; Alesse, E.; Matricardi, S.; Zafar, F.; Ullah, E.; Afzal, E.; Rahman, F.; Ahmed, M. M.; Parisi, P.; Spalice, A.; De Filippo, M.; Licari, A.; Trebbi, E.; Romano, F.; Heimer, G.; Al-Khawaja, I.; Al-Mutairi, F.; Alkuraya, F. S.; Rizig, M.; Shashkin, C.; Zharkynbekova, N.; Koneyev, K.; Bertoli-Avella, A.; Pagnamenta, A. T.; Niceta, M.; Battini, R.; Corsello, A.; Leoni, C.; Chiarelli, F.; Dallapiccola, B.; Faqeih, E. A.; Tallur, K. K.; Alfadhel, M.; Alobeid, E.; Maddirevula, S.; Mankad, K.; Banka, S.; Ghayoor-Karimiani, E.; Tartaglia, M.; Chung, W. K.; Green, R.; Jepson, J. E. C.; Houlden, H.. - In: AMERICAN JOURNAL OF HUMAN GENETICS. - ISSN 0002-9297. - 111:1(2024), pp. 200-210. [10.1016/j.ajhg.2023.11.012]
Bi-allelic genetic variants in the translational GTPases GTPBP1 and GTPBP2 cause a distinct identical neurodevelopmental syndrome
Striano P.;Ferrara P.;Morello G.;Sisto A.;Di Francesco L.;Iacomino M.;Iughetti L.;Ramenghi L. A.;Alesse E.;Battini R.;Leoni C.;Chiarelli F.;
2024
Abstract
The homologous genes GTPBP1 and GTPBP2 encode GTP-binding proteins 1 and 2, which are involved in ribosomal homeostasis. Pathogenic variants in GTPBP2 were recently shown to be an ultra-rare cause of neurodegenerative or neurodevelopmental disorders (NDDs). Until now, no human phenotype has been linked to GTPBP1. Here, we describe individuals carrying bi-allelic GTPBP1 variants that display an identical phenotype with GTPBP2 and characterize the overall spectrum of GTP-binding protein (1/2)-related disorders. In this study, 20 individuals from 16 families with distinct NDDs and syndromic facial features were investigated by whole-exome (WES) or whole-genome (WGS) sequencing. To assess the functional impact of the identified genetic variants, semi-quantitative PCR, western blot, and ribosome profiling assays were performed in fibroblasts from affected individuals. We also investigated the effect of reducing expression of CG2017, an ortholog of human GTPBP1/2, in the fruit fly Drosophila melanogaster. Individuals with bi-allelic GTPBP1 or GTPBP2 variants presented with microcephaly, profound neurodevelopmental impairment, pathognomonic craniofacial features, and ectodermal defects. Abnormal vision and/or hearing, progressive spasticity, choreoathetoid movements, refractory epilepsy, and brain atrophy were part of the core phenotype of this syndrome. Cell line studies identified a loss-of-function (LoF) impact of the disease-associated variants but no significant abnormalities on ribosome profiling. Reduced expression of CG2017 isoforms was associated with locomotor impairment in Drosophila. In conclusion, bi-allelic GTPBP1 and GTPBP2 LoF variants cause an identical, distinct neurodevelopmental syndrome. Mutant CG2017 knockout flies display motor impairment, highlighting the conserved role for GTP-binding proteins in CNS development across species.
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