%0 Journal Article
%T Heterozygous RNF13 Gain-of-Function Variants Are Associated with Congenital Microcephaly, Epileptic Encephalopathy, Blindness, and Failure to Thrive
%A Anna De Grassi
%A Avraham Shaag
%A Ciro Leonardo Pierri
%A Claudia M. Nicolae
%A Giuseppe Punzi
%A Grace J. Noh
%A Jennifer E. Burton
%A Jessica Bischetsrieder
%A Orly Elpeleg
%A Simon Edvardson
%J Archive of "American Journal of Human Genetics".
%D 2019
%R 10.1016/j.ajhg.2018.11.018
%X Accumulation of unfolded proteins in the endoplasmic reticulum (ER) initiates a stress response mechanism to clear out the unfolded proteins by either facilitating their re-folding or inducing their degradation. When this fails, an apoptotic cascade is initiated so that the affected cell is eliminated. IRE1¦Á is a critical sensor of the unfolded-protein response, essential for initiating the apoptotic signaling. Here, we report an infantile neurodegenerative disorder associated with enhanced activation of IRE1¦Á and increased apoptosis. Three unrelated affected individuals with congenital microcephaly, infantile epileptic encephalopathy, and profound developmental delay were found to carry heterozygous variants (c.932T>C [p.Leu311Ser] or c.935T>C [p.Leu312Pro]) in RNF13, which codes for an IRE1¦Á-interacting protein. Structural modeling predicted that the variants, located on the surface of the protein, would not alter overall protein folding. Accordingly, the abundance of RNF13 and IRE1¦Á was not altered in affected individuals¡¯ cells. However, both IRE1¦Á-mediated stress signaling and stress-induced apoptosis were increased in affected individuals¡¯ cells. These results indicate that the RNF13 variants confer gain of function to the encoded protein and thereby lead to altered signaling of the ER stress response associated with severe neurodegeneration in infancy
%K RNF13
%K microcephaly
%K epilepsy
%K XBP1 splicing
%K ER stress
%U https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6323416/