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Oh, R.Y.* ; Deshwar, A.R.* ; Marwaha, A.* ; Sabha, N.* ; Tropak, M.* ; Hou, H.* ; Yuki, K.E.* ; Wilson, M.D.* ; Rump, P.* ; Lunsing, R.* ; Elserafy, N.* ; Chung, C.W.T.* ; Hewson, S.* ; Klein-Rodewald, T. ; Calzada-Wack, J. ; Sanz-Moreno, A. ; Kraiger, M. ; Marschall, S. ; Fuchs, H. ; Gailus-Durner, V. ; Hrabě de Angelis, M. ; Dowling, J.J.* ; Schulze, A.*

Biallelic loss-of-function variants in RABGAP1 cause a novel neurodevelopmental syndrome.

Genet. Med. 24, 2399-2407 (2022)
DOI PMC
Open Access Green möglich sobald Postprint bei der ZB eingereicht worden ist.
PURPOSE: RABGAP1 is a GTPase-activating protein implicated in a variety of cellular and molecular processes, including mitosis, cell migration, vesicular trafficking, and mTOR signaling. There are no known Mendelian diseases caused by variants in RABGAP1. METHODS: Through GeneMatcher, we identified 5 patients from 3 unrelated families with homozygous variants in the RABGAP1 gene found on exome sequencing. We established lymphoblastoid cells lines derived from an affected individual and her parents and performed RNA sequencing and functional studies. Rabgap1 knockout mice were generated and phenotyped. RESULTS: We report 5 patients presenting with a common constellation of features, including global developmental delay/intellectual disability, microcephaly, bilateral sensorineural hearing loss, and seizures, as well as overlapping dysmorphic features. Neuroimaging revealed common features, including delayed myelination, white matter volume loss, ventriculomegaly, and thinning of the corpus callosum. Functional analysis of patient cells revealed downregulated mTOR signaling and abnormal localization of early endosomes and lysosomes. Rabgap1 knockout mice exhibited several features in common with the patient cohort, including microcephaly, thinning of the corpus callosum, and ventriculomegaly. CONCLUSION: Collectively, our results provide evidence of a novel neurodevelopmental syndrome caused by biallelic loss-of-function variants in RABGAP1.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter Autosomal Recessive ; Gtpase-activating Protein ; Neurodevelopmental Syndrome ; Novel Mendelian Disorder; Golgi; Rab6; Transport; Protein; Complexes; Genetics
ISSN (print) / ISBN 1530-0366
e-ISSN 1098-3600
Zeitschrift Genetics in Medicine
Quellenangaben Band: 24, Heft: 11, Seiten: 2399-2407 Artikelnummer: , Supplement: ,
Verlag Lippincott Williams & Wilkins
Verlagsort Baltimore, Md.
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Experimental Genetics (IEG)
Förderungen Bundesministerium für Bildung und Forschung
German Center for Diabetes Research
DZD