UBR5 mutations
UBR5(Ubiquitin-Protein Ligase E3 Component N-Recognin 5) is highly conserved and essential for mammalian development. UBR5modulates DNA damage response and transcription. The human UBR5gene is located on chromosome 8q22.3 and has 59 exons, encoding approximately 10 kb mRNA and >300 kDa protein. Monoallelic and biallelic pathogenic variants in UBR5are distributed throughout the coding sequence with no specific hot spots.
Genotype-phenotype correlation
There is no genotype-phenotype correlation for UBR5-related neurodevelopmental disorders.
Molecular-Pathomechanistic link
• Pathogenic potential loss of UBR5function (given the nonsense and splice site variant, haploinsufficiency is the proposed disease mechanism)
• Knocking out ubr-5 in C. elegans resulted in a lower movement score compared to the wild type, supporting a role for UBR5in neurodevelopment.
• Using an in vitro autoubiquitination assay and confocal microscopy for the human protein, many of the proband derived variants displayed reduced ubiquitination activity and altered cellular localization compared to the wild type.
Diagnostic testing
Variants were identified by trio exome or genome sequencing. The cohort was assembled with the help of Matchmaker Exchange platform tools.
UBR5