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Li, C.* ; Beauregard-Lacroix, E.* ; Kondratev, C.* ; Rousseau, J.* ; Heo, A.J.* ; Neas, K.* ; Graham, B.H.* ; Rosenfeld, J.A.* ; Bacino, C.A.* ; Wagner, M. ; Wenzel, M.* ; Al Mutairi, F.* ; Al Deiab, H.* ; Gleeson, J.G.* ; Stanley, V.* ; Zaki, M.S.* ; Kwon, Y.T.* ; Leroux, M.R.* ; Campeau, P.M.*

UBR7 functions with UBR5 in the Notch signaling pathway and is involved in a neurodevelopmental syndrome with epilepsy, ptosis, and hypothyroidism.

Am. J. Hum. Genet. 108, 134-147 (2021)
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The ubiquitin-proteasome system facilitates the degradation of unstable or damaged proteins. UBR1–7, which are members of hundreds of E3 ubiquitin ligases, recognize and regulate the half-life of specific proteins on the basis of their N-terminal sequences (“N-end rule”). In seven individuals with intellectual disability, epilepsy, ptosis, hypothyroidism, and genital anomalies, we uncovered bi-allelic variants in UBR7. Their phenotype differs significantly from that of Johanson-Blizzard syndrome (JBS), which is caused by bi-allelic variants in UBR1, notably by the presence of epilepsy and the absence of exocrine pancreatic insufficiency and hypoplasia of nasal alae. While the mechanistic etiology of JBS remains uncertain, mutation of both Ubr1 and Ubr2 in the mouse or of the C. elegans UBR5 ortholog results in Notch signaling defects. Consistent with a potential role in Notch signaling, C. elegans ubr-7 expression partially overlaps with that of ubr-5, including in neurons, as well as the distal tip cell that plays a crucial role in signaling to germline stem cells via the Notch signaling pathway. Analysis of ubr-5 and ubr-7 single mutants and double mutants revealed genetic interactions with the Notch receptor gene glp-1 that influenced development and embryo formation. Collectively, our findings further implicate the UBR protein family and the Notch signaling pathway in a neurodevelopmental syndrome with epilepsy, ptosis, and hypothyroidism that differs from JBS. Further studies exploring a potential role in histone regulation are warranted given clinical overlap with KAT6B disorders and the interaction of UBR7 and UBR5 with histones.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Epigenetic ; Epilepsy ; Hypothyroidism ; Kat6b ; Notch ; Ptosis ; Ubr-5 ; Ubr-7 ; Ubr5 ; Ubr7; E3 Ubiquitin Ligases; End Rule Pathway; Mental-retardation; Mice Lacking; Ataxia; Ubiquitylation; Proteins; Insights; Reveals; Disease
ISSN (print) / ISBN 0002-9297
e-ISSN 1537-6605
Quellenangaben Volume: 108, Issue: 1, Pages: 134-147 Article Number: , Supplement: ,
Publisher Elsevier
Publishing Place New York, NY
Reviewing status Peer reviewed
Grants National Research Foundation (NRF) - MSIP
Fonds de recherche du Quebec-Sante (FRQS)
Michael Smith Foundation for Health Research (MSFHR)
Canadian Rare Diseases: Models and Mechanisms Network (Genome Canada)
Canadian Rare Diseases: Models and Mechanisms Network (CIHR)
Canadian Institutes of Health Research (CIHR)