Bi-allelic genetic variants in the translational GTPases GTPBP1 and GTPBP2 cause a distinct identical neurodevelopmental syndrome.

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. Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.

Citation

Vincenzo Salpietro, Reza Maroofian, Maha S Zaki, Jamie Wangen, Andrea Ciolfi, Sabina Barresi, Stephanie Efthymiou, Angelique Lamaze, Gabriel N Aughey, Fuad Al Mutairi, Aboulfazl Rad, Clarissa Rocca, Elisa Calì, Andrea Accogli, Federico Zara, Pasquale Striano, Majid Mojarrad, Huma Tariq, Edoardo Giacopuzzi, Jenny C Taylor, Gabriela Oprea, Volha Skrahina, Khalil Ur Rehman, Marwa Abd Elmaksoud, Mahmoud Bassiony, Huda G El Said, Mohamed S Abdel-Hamid, Maha Al Shalan, Gohun Seo, Sohyun Kim, Hane Lee, Rin Khang, Mahmoud Y Issa, Hasnaa M Elbendary, Karima Rafat, Nikolaos M Marinakis, Joanne Traeger-Synodinos, Athina Ververi, Mara Sourmpi, Atieh Eslahi, Farhad Khadivi Zand, Mehran Beiraghi Toosi, Meisam Babaei, Adam Jackson, SYNAPS Study Group, Aida Bertoli-Avella, Alistair T Pagnamenta, Marcello Niceta, Roberta Battini, Antonio Corsello, Chiara Leoni, Francesco Chiarelli, Bruno Dallapiccola, Eissa Ali Faqeih, Krishnaraya K Tallur, Majid Alfadhel, Eman Alobeid, Sateesh Maddirevula, Kshitij Mankad, Siddharth Banka, Ehsan Ghayoor-Karimiani, Marco Tartaglia, Wendy K Chung, Rachel Green, Fowzan S Alkuraya, James E C Jepson, Henry Houlden. Bi-allelic genetic variants in the translational GTPases GTPBP1 and GTPBP2 cause a distinct identical neurodevelopmental syndrome. American journal of human genetics. 2024 Jan 04;111(1):200-210

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PMID: 38118446

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