Nathan Cummings Professor and Head, Laboratory of Neurogenetics and Development; Director, Center for Neurogenetics; Chair, Neuroscience Graduate Program; Weill Cornell Medical College
Dr. Ross reports no financial relationships relevant to this field of study.
SYNOPSIS: Genetic mutations that can modify post-translational proteins and their interactions may result in serious developmental disorders of the brain. Ufmylation is such a process, and mutations in the genes that regulate this process may have profound effects on the developing brain.
SOURCE: Nahorski MS, Maddirevula S, Ishimura R, et al. Biallelic UFM1 and UFC1 mutations expand the essential role of ufmylation in brain development. Brain 2018; Jun 2. doi/10.1093/brain/awy135/5032368. [Epub ahead of print].
Numerous single-gene mutations are known that cause microcephaly, with infantile encephalopathy manifested by severe global developmental delay and epilepsy. The report by Nahorski and colleagues is unusual, as it provides a first functionally verified example of a human brain developmental disorder caused by recessive mutation that affects a still rather esoteric pathway for post-translational modification of proteins called “ufmylation.”
The biochemical modification of proteins after they are translated from RNA greatly expands the actions of modified proteins by altering their stability, subcellular localization, and protein-protein interactions. Ufmylation is carried out in a pathway similar to ubiquitination, requiring participation of activating, conjugating, and ligating enzymes that are called ubiquitin-like proteins (UBLs). Ubiquitin-fold modifier 1 (UFM1) is a 9.1 kDa (73 amino acids) protein that resembles ubiquitin and is among the UBL1 proteins like SUMO that get conjugated to their target proteins. The ufmylation pathway produces covalent attachment of UFM1 to its target proteins through the actions of E1-activating enzyme UBA5, followed by E2 conjugation by UFC1, and finally transfer of UFM1 to its target by formation of a thioester bond catalyzed by UFL1 ligase. Diseases previously associated with ufmylation include cancer, diabetes, ischemic heart disease, and alcoholic liver disease.
Several significant insights were obtained in this study. Exome sequencing was used to identify UFM1 missense mutations in four children from two unrelated Sudanese families and UFC1 missense mutations in three Saudi families and one Swiss family with eight affected members. Thus, the connection between mutations in UFM1 and UFC1 and brain development is made on genetic grounds. The investigators take the study further by showing that these variants produce hypomorphic dysfunction of the UFM system by altered UBA5-UFM1 mutant interaction, and reduced thioester formation by the mutant UFC1 versions. In fly, worm, and zebrafish models, ablation of UBA5 causes lethality while a brain-specific, conditional knockout of UBA5 in mice produces microcephaly and evidence of increased neural apoptosis, suggesting that ufmylation is important for neuronal development and survival. Therefore, Nahorski et al tested the possibility of whether the altered ufmylation due to the discovered missense mutations resulted in endoplasmic reticulum stress-mediated apoptotic cell death. The authors concluded that stress-induced apoptosis is not the underlying cause of pathogenesis in these families. Thus, it appears that the partial loss of ufmylation pathway function may disrupt neurodevelopment through effects on brain proteins that interact with UFC1 or other pathway components.
The report is significant as a striking example of the importance of dysfunctional post-translational processing of proteins as a potential cause of neurological disease. It follows that targeting post-translational modifications beyond phosphorylation may yield exciting new treatments for a number of neurological disorders.