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AlAbdi, L.* ; Desbois, M.* ; Rusnac, D.V.* ; Sulaiman, R.A.* ; Rosenfeld, J.A.* ; Lalani, S.* ; Murdock, D.R.* ; Burrage, L.C.* ; Undiagnosed Diseases Network* ; Billie Au, P.Y.* ; Towner, S.* ; Wilson, W.G.* ; Wong, L.* ; Brunet, T. ; Strobl-Wildemann, G.* ; Burton, J.E.* ; Hoganson, G.* ; McWalter, K.* ; Begtrup, A.* ; Zarate, Y.A.* ; Christensen, E.L.* ; Opperman, K.J.* ; Giles, A.C.* ; Helaby, R.* ; Kania, A.* ; Zheng, N.* ; Grill, B.* ; Alkuraya, F.S.*

Loss-of-function variants in MYCBP2 cause neurobehavioural phenotypes and corpus callosum defects.

Brain 146, 1373-1387 (2022)
Verlagsversion Postprint DOI PMC
Open Access Gold (Paid Option)
The corpus callosum is a bundle of axon fibers that connects the two hemispheres of the brain. Neurodevelopmental disorders that feature dysgenesis of the corpus callosum as a core phenotype offer a valuable window into pathology derived from abnormal axon development. Here, we describe a cohort of eight patients with a neurodevelopmental disorder characterized by a range of deficits including corpus callosum abnormalities, developmental delay, intellectual disability, epilepsy, and autistic features. Each patient harbored a distinct de novo variant in MYCBP2, a gene encoding an atypical RING ubiquitin ligase and signaling hub with evolutionarily conserved functions in axon development. We used CRISPR/Cas9 gene editing to introduce disease-associated variants into conserved residues in the C. elegans MYCBP2 ortholog, RPM-1, and evaluated functional outcomes in vivo. Consistent with variable phenotypes in patients with MYCBP2 variants, C. elegans carrying the corresponding human mutations in rpm-1 displayed axonal and behavioral abnormalities including altered habituation. Furthermore, abnormal axonal accumulation of the autophagy marker LGG-1/LC3 occurred in variants that affect RPM-1 ubiquitin ligase activity. Functional genetic outcomes from anatomical, cell biological and behavioral readouts indicate that MYCBP2 variants are likely to result in loss of function. Collectively, our results from multiple human patients and CRISPR gene editing with an in vivo animal model support a direct link between MYCBP2 and a human neurodevelopmental spectrum disorder that we term, MYCBP2-related developmental delay with corpus callosum defects (MDCD).
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter Mycbp2 ; Phr1 ; Corpus Callosum ; Epilepsy ; Habituation ; Neurodevelopmental Disorder; Regulates Axon Outgrowth; Neurodevelopmental Disorders; Formation Reveals; Protein; Rpm-1; Mutations; Agenesis; Ligase; Pam; Phr1
ISSN (print) / ISBN 0006-8950
e-ISSN 1460-2156
Zeitschrift Brain: A Journal of Neurology
Quellenangaben Band: 146, Heft: 4, Seiten: 1373-1387 Artikelnummer: , Supplement: ,
Verlag Oxford University Press
Verlagsort Great Clarendon St, Oxford Ox2 6dp, England
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Neurogenomics (ING)