David B Beck et al have discovered a new dysregulated neurodevelopmental pathway that can cause developmental delays and malformations of the brain, heart and facial features. The researchers named the previously unidentified disorder as linkage-specific-deubiquitylation-deficiency-induced embryonic defects syndrome (LINKED). The team studied 10 patients with multiple congenital anomalies and found that the defect was caused by a mutated version of the OTUD5 gene. The OTUD5 gene carried instructions for making the OTUD5 enzyme essential for ubiquitylation which helped the stem cells to become specific cell types in the early stages of embryo development. The mutated hemizygous variants in OTUD5 gene encoded a K48/K63 linkage–specific deubiquitylase enzyme. The team found that chromatin remodellers targeted by OTUD5 helped enhance the expression of genes that controlled the cell fate of neural precursors during embryogenesis.
When OTUD5 is mutated, its protective function is lost and the chromatin remodellers are destroyed, leading to abnormal development of neural precursors and neural crest cells causing birth defects.
Source: Science Advances 20 Jan 2021: Vol. 7, no. 4, eabe2116 DOI: 10.1126/sciadv.abe2116 https://advances.sciencemag.org/content/7/4/eabe2116