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

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

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)179-185
Number of pages7
JournalAmerican Journal of Human Genetics
Volume104
Issue number1
DOIs
StatePublished - Jan 3 2019

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Failure to Thrive
Microcephaly
Brain Diseases
Blindness
Protein Unfolding
Apoptosis
Unfolded Protein Response
Endoplasmic Reticulum Stress
Protein Folding
Endoplasmic Reticulum
Neurodegenerative Diseases
Membrane Proteins
Proteins

All Science Journal Classification (ASJC) codes

  • Genetics
  • Genetics(clinical)

Cite this

Edvardson, Simon ; Nicolae, Claudia ; Noh, Grace J. ; Burton, Jennifer E. ; Punzi, Giuseppe ; Shaag, Avraham ; Bischetsrieder, Jessica ; De Grassi, Anna ; Pierri, Ciro Leonardo ; Elpeleg, Orly ; Moldovan, George-Lucian. / Heterozygous RNF13 Gain-of-Function Variants Are Associated with Congenital Microcephaly, Epileptic Encephalopathy, Blindness, and Failure to Thrive. In: American Journal of Human Genetics. 2019 ; Vol. 104, No. 1. pp. 179-185.
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Heterozygous RNF13 Gain-of-Function Variants Are Associated with Congenital Microcephaly, Epileptic Encephalopathy, Blindness, and Failure to Thrive. / Edvardson, Simon; Nicolae, Claudia; Noh, Grace J.; Burton, Jennifer E.; Punzi, Giuseppe; Shaag, Avraham; Bischetsrieder, Jessica; De Grassi, Anna; Pierri, Ciro Leonardo; Elpeleg, Orly; Moldovan, George-Lucian.

In: American Journal of Human Genetics, Vol. 104, No. 1, 03.01.2019, p. 179-185.

Research output: Contribution to journalArticle

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AU - Burton, Jennifer E.

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AU - Moldovan, George-Lucian

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