Heterozygous RNF13 Gain-of-Function Variants Are Associated with Congenital Microcephaly, Epileptic Encephalopathy, Blindness, and Failure to Thrive
| Autor: | Orly Elpeleg, Claudia M. Nicolae, Anna De Grassi, Jessica Bischetsrieder, Simon Edvardson, Giuseppe Punzi, Jennifer Burton, George Lucian Moldovan, Ciro Leonardo Pierri, Grace J. Noh, Avraham Shaag |
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| Rok vydání: | 2019 |
| Předmět: |
Male
Models Molecular 0301 basic medicine Heterozygote Microcephaly Developmental Disabilities Ubiquitin-Protein Ligases Cell Apoptosis Biology Blindness 03 medical and health sciences Epilepsy 0302 clinical medicine Report Genetics medicine Humans Amino Acid Sequence Child Genetics (clinical) Endoplasmic reticulum Neurodegeneration Infant Endoplasmic Reticulum Stress medicine.disease Failure to Thrive Cell biology 030104 developmental biology medicine.anatomical_structure Child Preschool Gain of Function Mutation Failure to thrive Unfolded Protein Response Unfolded protein response medicine.symptom Spasms Infantile 030217 neurology & neurosurgery |
| Zdroj: | The American Journal of Human Genetics. 104:179-185 |
| ISSN: | 0002-9297 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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