Bi-allelic genetic variants in the translational GTPases GTPBP1 and GTPBP2 cause a distinct identical neurodevelopmental syndrome.
GREND syndrome
GTPBP1
GTPBP2
NBIA
animal models
ectodermal disorders
neurodegeneration
neurodevelopmental disorders
ribosome stalling
ribosomopathies
Journal
American journal of human genetics
ISSN: 1537-6605
Titre abrégé: Am J Hum Genet
Pays: United States
ID NLM: 0370475
Informations de publication
Date de publication:
04 Jan 2024
04 Jan 2024
Historique:
received:
15
05
2023
revised:
27
11
2023
accepted:
29
11
2023
medline:
8
1
2024
pubmed:
21
12
2023
entrez:
20
12
2023
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 38118446
pii: S0002-9297(23)00430-5
doi: 10.1016/j.ajhg.2023.11.012
pmc: PMC10806450
pii:
doi:
Substances chimiques
GTP Phosphohydrolases
EC 3.6.1.-
GTP-Binding Proteins
EC 3.6.1.-
GTPBP2 protein, human
EC 3.6.1.-
GTPBP1 protein, human
EC 3.6.5.2
Drosophila Proteins
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
200-210Subventions
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/S01165X/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/V03118X/1
Pays : United Kingdom
Investigateurs
Michael G Hannah
(MG)
Enrico Bugiardini
(E)
Enrico Bertini
(E)
Yamna Kriouile
(Y)
Mohamed El-Khorassani
(M)
Mhammed Aguennouz
(M)
Stanislav Groppa
(S)
Blagovesta M Karashova
(BM)
Jatinder S Goraya
(JS)
Tipu Sultan
(T)
Daniela Avdjieva
(D)
Hadil Kathom
(H)
Radka Tincheva
(R)
Selina Banu
(S)
Pierangelo Veggiotti
(P)
Alberto Verrotti
(A)
Marcello Lanari
(M)
Salvatore Savasta
(S)
Alfons Macaya
(A)
Barbara Garavaglia
(B)
Eugenia Borgione
(E)
Savvas Papacostas
(S)
Michail Vikelis
(M)
Viorica Chelban
(V)
Rauan Kaiyrzhanov
(R)
Andrea Cortese
(A)
Roisin Sullivan
(R)
Eleni Z Papanicolaou
(EZ)
Efthymios Dardiotis
(E)
Shazia Maqbool
(S)
Shahnaz Ibrahim
(S)
Salman Kirmani
(S)
Nuzhat N Rana
(NN)
Osama Atawneh
(O)
Shen-Yang Lim
(SY)
Gian V Zuccotti
(GV)
Gian L Marseglia
(GL)
Susanna Esposito
(S)
Farooq Shaikh
(F)
Paola Cogo
(P)
Giovanni Corsello
(G)
Salvatore Mangano
(S)
Rosaria Nardello
(R)
Donato Mangano
(D)
Annarita Scardamaglia
(A)
George Koutsis
(G)
Carmela Scuderi
(C)
Eugenia Borgione
(E)
Pietro Ferrara
(P)
Giovanna Morello
(G)
Massimo Zollo
(M)
Roberto Berni-Canani
(R)
Luigi M Terracciano
(LM)
Antonio Sisto
(A)
Sandra Di Fabio
(S)
Federica Strano
(F)
Giovanna Scorrano
(G)
Saverio Di Bella
(S)
Ludovica Di Francesco
(L)
Ganieva Manizha
(G)
Maksud Isrofilov
(M)
Ulviyya Guliyeva
(U)
Kamran Salayev
(K)
Samson Khachatryan
(S)
Georgia Xiromerisiou
(G)
Cleanthe Spanaki
(C)
Chiara Fiorillo
(C)
Michele Iacomino
(M)
Eugenio Gaudio
(E)
Francina Munell
(F)
Antonella Gagliano
(A)
Farida Jan
(F)
Roberto Chimenz
(R)
Eloisa Gitto
(E)
Lorenzo Iughetti
(L)
Gabriella Di Rosa
(G)
Mohamad Maghnie
(M)
Massimo Pettoello-Mantovani
(M)
Neerja Gupta
(N)
Madhulika Kabra
(M)
Hanene Benrhouma
(H)
Meriem Tazir
(M)
Gabriella Bottone
(G)
Giovanni Farello
(G)
Maurizio Delvecchio
(M)
Giulio Di-Donato
(G)
Makram Obeid
(M)
Sophia Bakhtadze
(S)
Nebal W Saadi
(NW)
Michele Miraglia-Del-Giudice
(M)
Rita Maccarone
(R)
Maha S Zaki
(MS)
Chahnez C Triki
(CC)
Majdi Kara
(M)
Ehsan G Karimiani
(EG)
Ahmed M Salih
(AM)
Luca A Ramenghi
(LA)
Marco Seri
(M)
Giovanna Di-Falco
(G)
Luana Mandarà
(L)
Giuseppe Barrano
(G)
Maurizio Elisa
(M)
Enrico Cherubini
(E)
Francesca F Operto
(FF)
Mariella Valenzise
(M)
Antonino Cattaneo
(A)
Francesca Zazzeroni
(F)
Edoardo Alesse
(E)
Sara Matricardi
(S)
Faisal Zafar
(F)
Ehsan Ullah
(E)
Erum Afzal
(E)
Fatima Rahman
(F)
Muhammad M Ahmed
(MM)
Pasquale Parisi
(P)
Alberto Spalice
(A)
Maria De Filippo
(M)
Amelia Licari
(A)
Edoardo Trebbi
(E)
Ferdinando Romano
(F)
Gali Heimer
(G)
Issam Al-Khawaja
(I)
Fuad Al-Mutairi
(F)
Fowzan S Alkuraya
(FS)
Mie Rizig
(M)
Chingiz Shashkin
(C)
Nazira Zharkynbekova
(N)
Kairgali Koneyev
(K)
Informations de copyright
Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests The authors declare no competing interests.
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