Heterozygous RNF13 Gain-of-Function Variants Are Associated with Congenital Microcephaly, Epileptic Encephalopathy, Blindness, and Failure to Thrive

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 eliminat...

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Bibliographic Details
Published in:American journal of human genetics 2019-01, Vol.104 (1), p.179-185
Main Authors: Edvardson, Simon, Nicolae, Claudia M., Noh, Grace J., Burton, Jennifer E., Punzi, Giuseppe, Shaag, Avraham, Bischetsrieder, Jessica, De Grassi, Anna, Pierri, Ciro Leonardo, Elpeleg, Orly, Moldovan, George-Lucian
Format: Article
Language:English
Subjects:
Amino Acid Sequence
Apoptosis
Blindness - congenital
Blindness - genetics
Child
Child, Preschool
Developmental Disabilities - genetics
Endoplasmic Reticulum Stress
epilepsy
ER stress
Failure to Thrive - genetics
Gain of Function Mutation
Heterozygote
Humans
Infant
Male
microcephaly
Microcephaly - genetics
Models, Molecular
RNF13
Spasms, Infantile - congenital
Spasms, Infantile - genetics
Ubiquitin-Protein Ligases - chemistry
Ubiquitin-Protein Ligases - genetics
Unfolded Protein Response
XBP1 splicing
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Summary: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. IRE1α 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 IRE1α 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 IRE1α-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 IRE1α was not altered in affected individuals’ cells. However, both IRE1α-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.
ISSN:0002-9297
1537-6605
DOI:10.1016/j.ajhg.2018.11.018