UBR7 functions with UBR5 in the Notch signaling pathway and is involved in a neurodevelopmental syndrome with epilepsy, ptosis, and hypothyroidism
Autor: | Yong Tae Kwon, Ah Jung Heo, Jill A. Rosenfeld, Eliane Beauregard-Lacroix, Carlos A. Bacino, Philippe M. Campeau, Maren Wenzel, Valentina Stanley, Hamad Al Deiab, Michel R. Leroux, Christine Kondratev, Justine Rousseau, Katherine Neas, Brett H. Graham, Matias Wagner, Chunmei Li, Fuad Al Mutairi, Joseph G. Gleeson, Maha S. Zaki |
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Jazyk: | angličtina |
Rok vydání: | 2021 |
Předmět: |
0301 basic medicine
Proteasome Endopeptidase Complex Hearing Loss Sensorineural Ubiquitin-Protein Ligases Notch signaling pathway Nose medicine.disease_cause Article Germline Epigenetic Epilepsy Hypothyroidism Kat6b Notch Ptosis Ubr-5 Ubr-7 Ubr5 Ubr7 Cell Line Anus Imperforate Histones Mice 03 medical and health sciences 0302 clinical medicine Ubiquitin Ectodermal Dysplasia Intellectual Disability Genetics medicine Animals Humans Epigenetics Caenorhabditis elegans Growth Disorders Genetics (clinical) Mutation Receptors Notch biology Pancreatic Diseases medicine.disease Phenotype Cell biology HEK293 Cells 030104 developmental biology Histone Neurodevelopmental Disorders biology.protein 030217 neurology & neurosurgery Signal Transduction |
Zdroj: | Am. J. Hum. Genet. 108, 134-147 (2021) Am J Hum Genet |
Popis: | Summary 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. |
Databáze: | OpenAIRE |
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