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Heterozygous RNF13 Gain-of-Function Variants Are Associated with Congenital Microcephaly, Epileptic Encephalopathy, Blindness, and Failure to Thrive
- Source :
- The American Journal of Human Genetics. 104:179-185
- Publication Year :
- 2019
- Publisher :
- Elsevier BV, 2019.
-
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.
- Subjects :
- 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
Subjects
Details
- ISSN :
- 00029297
- Volume :
- 104
- Database :
- OpenAIRE
- Journal :
- The American Journal of Human Genetics
- Accession number :
- edsair.doi.dedup.....5ac9ae6a1ccb0bedc0595d1cff48d9eb