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., Calì, 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., SYNAPS Study Group, , 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., Alkuraya, F.S., Jepson, J.E.C., Houlden, H. (2024). Bi-allelic genetic variants in the translational GTPases GTPBP1 and GTPBP2 cause a distinct identical neurodevelopmental syndrome.  Am. J. Hum. Genet. 111(1): 200--210.

FBrf0258488

Research paper

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.

PMC10806450 (PMC) (EuropePMC)