hnRNPH2 gain-of-function mutations reveal therapeutic strategies and a role for RNA granules in neurodevelopmental disorders
Benjamin A. Kelvington, Ted Abel
Benjamin A. Kelvington, Ted Abel
Published July 17, 2023
Citation Information: J Clin Invest. 2023;133(14):e171499. https://doi.org/10.1172/JCI171499.
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Commentary

hnRNPH2 gain-of-function mutations reveal therapeutic strategies and a role for RNA granules in neurodevelopmental disorders

Abstract

hnRNPH2-related neurodevelopmental disorder (NDD) is caused by mutations in the HNRNPH2 gene and is associated with substantial challenges, including developmental delay, intellectual disability, growth delay, and epilepsy. There is currently no therapeutic intervention available to those with hnRNPH2-related NDD that addresses its underlying mechanisms. In this issue of the JCI, Korff et al. studied specific gain-of-function mutations associated with hnRNPH2-related NDD, with the help of mouse models that recapitulate key features of the condition in humans. Their work paves the way for therapeutic approaches that aim to reduce the expression of mutant hnRNPH2 and highlights a role for disrupted RNA granules in neurodevelopmental and neurodegenerative disorders.

Authors

Benjamin A. Kelvington, Ted Abel

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Figure 1

The consequences of NDD-associated mutations in hnRNPH2 include altered localization, disrupted gene expression, and NDD-relevant phenotypes.

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The consequences of NDD-associated mutations in hnRNPH2 include altered ...
The presence of mutant hnRNPH2 inhibits genetic compensation by hnRNPH1. Reduced nuclear import of hnRNPH2 mutants leads to their incorporation into cytoplasmic RNA granules. Mutant hnRNPH2-containing RNA granules alter patterns of gene expression that ultimately lead to the phenotypes associated with hnRNPH2-related NDD. The expression of mutant hnRNPH2 may be reduced using an antisense oligonucleotide (ASO) as a therapeutic strategy.