biostudies-literatureLi CFonds de Recherche du Québec - SantéMichael Smith Foundation for Health ResearchMinistry of Science, ICT and Future PlanningNational Research FoundationGenome CanadaCanadian Institutes of Health ResearchCIHR134-147https://www.ebi.ac.uk/biostudies/studies/S-EPMC7820726biostudies-literatureUnknown108(1)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 UBRAmerican journal of human geneticsUBR7 functions with UBR5 in the Notch signaling pathway and is involved in a neurodevelopmental syndrome with epilepsy, ptosis, and hypothyroidism.PMC7820726NRF-2020R1A5A1019023MOP142243NRF-2016R1A2B3011389Kwon YTNeas KStanley VCampeau PMLi CRosenfeld JAAl Mutairi FGleeson JGHeo AJWagner MRousseau JKondratev CZaki MSLeroux MRBacino CABeauregard-Lacroix EGraham BHWenzel MAl Deiab HfalseUBR7 functions with UBR5 in the Notch signaling pathway and is involved in a neurodevelopmental syndrome with epilepsy, ptosis, and hypothyroidism.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 UBR2021-01-01T00:00:00Z2021 Jan2026-04-07T17:53:07.887Z2022-02-10T18:21:12.551ZS-EPMC78207263334045510.1016/j.ajhg.2020.11.018