| Title: |
Bi-allelic genetic variants in the translational GTPases GTPBP1 and GTPBP2 cause a distinct identical neurodevelopmental syndrome |
| Authors: |
Salpietro, Vincenzo; Maroofian, Reza; Zaki, Maha S.; Wangen, Jamie; Ciolfi, Andrea; Barresi, Sabina; Efthymiou, Stephanie; Lamaze, Angelique; Aughey, Gabriel N.; Al Mutairi, Fuad; Rad, Aboulfazl; Rocca, Clarissa; Calì, Elisa; Accogli, Andrea; Zara, Federico; Striano, Pasquale; Mojarrad, Majid; Tariq, Huma; Giacopuzzi, Edoardo; Taylor, Jenny C.; Oprea, Gabriela; Skrahina, Volha; Rehman, Khalil Ur; Abd Elmaksoud, Marwa; Bassiony, Mahmoud; El Said, Huda G.; Abdel-Hamid, Mohamed S.; Al Shalan, Maha; Seo, Gohun; Kim, Sohyun; Lee, Hane; Khang, Rin; Issa, Mahmoud Y.; Elbendary, Hasnaa M.; Rafat, Karima; Marinakis, Nikolaos M.; Traeger-Synodinos, Joanne; Ververi, Athina; Sourmpi, Mara; Eslahi, Atieh; Khadivi Zand, Farhad; Beiraghi Toosi, Mehran; Babaei, Meisam; Jackson, Adam; Hannah, Michael G.; Bugiardini, Enrico; Bertini, Enrico; Kriouile, Yamna; El-Khorassani, Mohamed; Aguennouz, Mhammed; Groppa, Stanislav; Karashova, Blagovesta M.; Goraya, Jatinder S.; Sultan, Tipu; Avdjieva, Daniela; Kathom, Hadil; Tincheva, Radka; Banu, Selina; Veggiotti, Pierangelo; Verrotti, Alberto; Lanari, Marcello; Savasta, Salvatore; Macaya, Alfons; Garavaglia, Barbara; Borgione, Eugenia; Papacostas, Savvas; Vikelis, Michail; Chelban, Viorica; Kaiyrzhanov, Rauan; Cortese, Andrea; Sullivan, Roisin; Papanicolaou, Eleni Z.; Dardiotis, Efthymios; Maqbool, Shazia; Ibrahim, Shahnaz; Kirmani, Salman; Rana, Nuzhat N.; Atawneh, Osama; Lim, Shen-Yang; Zuccotti, Gian V.; Marseglia, Gian L.; Esposito, Susanna; Shaikh, Farooq; Cogo, Paola; Corsello, Giovanni; Mangano, Salvatore; Nardello, Rosaria; Mangano, Donato; Scardamaglia, Annarita; Koutsis, George; Scuderi, Carmela; Ferrara, Pietro; Morello, Giovanna; Zollo, Massimo; Berni-Canani, Roberto; Terracciano, Luigi M.; Sisto, Antonio; Di Fabio, Sandra; Strano, Federica; Scorrano, Giovanna; Di Bella, Saverio; Di Francesco, Ludovica; Manizha, Ganieva; Isrofilov, Maksud; Guliyeva, Ulviyya; Salayev, Kamran; Khachatryan, Samson; Xiromerisiou, Georgia; Spanaki, Cleanthe; Fiorillo, Chiara; Iacomino, Michele; Gaudio, Eugenio; Munell, Francina; Gagliano, Antonella; Jan, Farida; Chimenz, Roberto; Gitto, Eloisa; Iughetti, Lorenzo; Di Rosa, Gabriella; Maghnie, Mohamad; Pettoello-Mantovani, Massimo; Gupta, Neerja; Kabra, Madhulika; Benrhouma, Hanene; Tazir, Meriem; Bottone, Gabriella; Farello, Giovanni; Delvecchio, Maurizio; Di-Donato, Giulio; Obeid, Makram; Bakhtadze, Sophia; Saadi, Nebal W.; Miraglia-Del-Giudice, Michele; Maccarone, Rita; Triki, Chahnez C.; Kara, Majdi; Karimiani, Ehsan G.; Salih, Ahmed M.; Ramenghi, Luca A.; Seri, Marco; Di-Falco, Giovanna; Mandarà, Luana; Barrano, Giuseppe; Elisa, Maurizio; Cherubini, Enrico; Operto, Francesca F.; Valenzise, Mariella; Cattaneo, Antonino; Zazzeroni, Francesca; Alesse, Edoardo; Matricardi, Sara; Zafar, Faisal; Ullah, Ehsan; Afzal, Erum; Rahman, Fatima; Ahmed, Muhammad M.; Parisi, Pasquale; Spalice, Alberto; De Filippo, Maria; Licari, Amelia; Trebbi, Edoardo; Romano, Ferdinando; Heimer, Gali; Al-Khawaja, Issam; Al-Mutairi, Fuad; Alkuraya, Fowzan S.; Rizig, Mie; Shashkin, Chingiz; Zharkynbekova, Nazira; Koneyev, Kairgali; Bertoli-Avella, Aida; Pagnamenta, Alistair T.; Niceta, Marcello; Battini, Roberta; Corsello, Antonio; Leoni, Chiara; Chiarelli, Francesco; Dallapiccola, Bruno; Faqeih, Eissa Ali; Tallur, Krishnaraya K.; Alfadhel, Majid; Alobeid, Eman; Maddirevula, Sateesh; Mankad, Kshitij; Banka, Siddharth; Ghayoor-Karimiani, Ehsan; Tartaglia, Marco; Chung, Wendy K.; Green, Rachel; Jepson, James E. C.; Houlden, Henry |
| Contributors: |
V. Salpietro; R. Maroofian; M.S. Zaki; J. Wangen; A. Ciolfi; S. Barresi; S. Efthymiou; A. Lamaze; G.N. Aughey; F. Al Mutairi; A. Rad; C. Rocca; E. Calì; A. Accogli; F. Zara; P. Striano; M. Mojarrad; H. Tariq; E. Giacopuzzi; J.C. Taylor; G. Oprea; V. Skrahina; K.U. Rehman; M. Abd Elmaksoud; M. Bassiony; H.G. El Said; M.S. Abdel-Hamid; M. Al Shalan; G. Seo; S. Kim; H. Lee; R. Khang; M.Y. Issa; H.M. Elbendary; K. Rafat; N.M. Marinaki; J. Traeger-Synodino; A. Ververi; M. Sourmpi; A. Eslahi; F. Khadivi Zand; M. Beiraghi Toosi; M. Babaei; A. Jackson; M.G. Hannah; E. Bugiardini; E. Bertini; Y. Kriouile; M. El-Khorassani; M. Aguennouz; S. Groppa; B.M. Karashova; J.S. Goraya; T. Sultan; D. Avdjieva; H. Kathom; R. Tincheva; S. Banu; P. Veggiotti; A. Verrotti; M. Lanari; S. Savasta; A. Macaya; B. Garavaglia; E. Borgione; S. Papacosta; M. Vikeli; V. Chelban; R. Kaiyrzhanov; A. Cortese; R. Sullivan; E.Z. Papanicolaou; E. Dardioti; S. Maqbool; S. Ibrahim; S. Kirmani; N.N. Rana; O. Atawneh; S. Lim; G.V. Zuccotti; G.L. Marseglia; S. Esposito; F. Shaikh; P. Cogo; G. Corsello; S. Mangano; R. Nardello; D. Mangano; A. Scardamaglia; G. Koutsi; C. Scuderi; P. Ferrara; G. Morello; M. Zollo; R. Berni-Canani; L.M. Terracciano; A. Sisto; S. Di Fabio; F. Strano |
| Publisher Information: |
Elsevier - Cell Press |
| Publication Year: |
2024 |
| Collection: |
The University of Milan: Archivio Istituzionale della Ricerca (AIR) |
| Subject Terms: |
GREND syndrome; GTPBP1; GTPBP2; NBIA; animal model; ectodermal disorder; neurodegeneration; neurodevelopmental disorder; ribosome stalling; ribosomopathies; Settore MEDS-20/A - Pediatria generale e specialistica |
| Description: |
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. |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| Relation: |
info:eu-repo/semantics/altIdentifier/pmid/38118446; info:eu-repo/semantics/altIdentifier/wos/WOS:001158522000001; volume:111; issue:1; firstpage:200; lastpage:210; numberofpages:11; journal:AMERICAN JOURNAL OF HUMAN GENETICS; https://hdl.handle.net/2434/1127347 |
| DOI: |
10.1016/j.ajhg.2023.11.012 |
| Availability: |
https://hdl.handle.net/2434/1127347; https://doi.org/10.1016/j.ajhg.2023.11.012 |
| Rights: |
info:eu-repo/semantics/openAccess ; license:Creative commons ; license uri:http://creativecommons.org/licenses/by/4.0/ |
| Accession Number: |
edsbas.DF0F0DA5 |
| Database: |
BASE |