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

Simon Edvardson; Claudia M Nicolae; Grace J Noh; Jennifer E Burton; Giuseppe Punzi; Avraham Shaag; Jessica Bischetsrieder; Anna De Grassi; Ciro Leonardo Pierri; Orly Elpeleg; George-Lucian Moldovan

doi:10.1016/j.ajhg.2018.11.018

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

Am J Hum Genet. 2019 Jan 3;104(1):179-185. doi: 10.1016/j.ajhg.2018.11.018. Epub 2018 Dec 27.

Authors

Affiliations

¹ Monique and Jacques Roboh Department of Genetic Research, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel; Pediatric Neurology Unit, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel.
² Department of Biochemistry and Molecular Biology, Pennsylvania State University College of Medicine, 500 University Drive, Hershey, PA 17033, USA.
³ Department of Genetics, Southern California Permanente Medical Group, Fontana, CA 92335, USA.
⁴ University of Illinois College of Medicine at Peoria, Illini Drive, Peoria, IL 61605, USA.
⁵ Laboratory of Biochemistry, Molecular and Computational Biology, Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, Bari 70125, Italy.
⁶ Monique and Jacques Roboh Department of Genetic Research, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel.
⁷ Monique and Jacques Roboh Department of Genetic Research, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel. Electronic address: elpeleg@hadassah.org.il.
⁸ Department of Biochemistry and Molecular Biology, Pennsylvania State University College of Medicine, 500 University Drive, Hershey, PA 17033, USA. Electronic address: gmoldovan@pennstatehealth.psu.edu.

Abstract

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.

Keywords: ER stress; RNF13; XBP1 splicing; epilepsy; microcephaly.

MeSH terms

Amino Acid Sequence
Apoptosis
Blindness / congenital*
Blindness / genetics*
Child
Child, Preschool
Developmental Disabilities / genetics
Endoplasmic Reticulum Stress
Failure to Thrive / genetics*
Gain of Function Mutation*
Heterozygote*
Humans
Infant
Male
Microcephaly / genetics*
Models, Molecular
Spasms, Infantile / congenital
Spasms, Infantile / genetics*
Ubiquitin-Protein Ligases / chemistry
Ubiquitin-Protein Ligases / genetics*
Unfolded Protein Response

Substances

RNF13 protein, human
Ubiquitin-Protein Ligases

Supplementary concepts

Infantile Epileptic-Dyskinetic Encephalopathy