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A murine model of hnRNPH2-related neurodevelopmental disorder reveals a mechanism for genetic compensation by Hnrnph1
Ane Korff, … , J. Paul Taylor, Hong Joo Kim
Ane Korff, … , J. Paul Taylor, Hong Joo Kim
Published July 17, 2023
Citation Information: J Clin Invest. 2023;133(14):e160309. https://doi.org/10.1172/JCI160309.
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Research Article Neuroscience Article has an altmetric score of 3

A murine model of hnRNPH2-related neurodevelopmental disorder reveals a mechanism for genetic compensation by Hnrnph1

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Abstract

Mutations in HNRNPH2 cause an X-linked neurodevelopmental disorder with features that include developmental delay, motor function deficits, and seizures. More than 90% of patients with hnRNPH2 have a missense mutation within or adjacent to the nuclear localization signal (NLS) of hnRNPH2. Here, we report that hnRNPH2 NLS mutations caused reduced interaction with the nuclear transport receptor Kapβ2 and resulted in modest cytoplasmic accumulation of hnRNPH2. We generated 2 knockin mouse models with human-equivalent mutations in Hnrnph2 as well as Hnrnph2-KO mice. Knockin mice recapitulated clinical features of the human disorder, including reduced survival in male mice, impaired motor and cognitive functions, and increased susceptibility to audiogenic seizures. In contrast, 2 independent lines of Hnrnph2-KO mice showed no detectable phenotypes. Notably, KO mice had upregulated expression of Hnrnph1, a paralog of Hnrnph2, whereas knockin mice failed to upregulate Hnrnph1. Thus, genetic compensation by Hnrnph1 may counteract the loss of hnRNPH2. These findings suggest that HNRNPH2-related disorder may be driven by a toxic gain of function or a complex loss of HNRNPH2 function with impaired compensation by HNRNPH1. The knockin mice described here are an important resource for preclinical studies to assess the therapeutic benefit of gene replacement or knockdown of mutant hnRNPH2.

Authors

Ane Korff, Xiaojing Yang, Kevin O’Donovan, Abner Gonzalez, Brett J.W. Teubner, Haruko Nakamura, James Messing, Fen Yang, Alexandre F. Carisey, Yong-Dong Wang, Tushar Patni, Heather Sheppard, Stanislav S. Zakharenko, Yuh Min Chook, J. Paul Taylor, Hong Joo Kim

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Figure 8

Spatiotemporal expression of Hnrnph1 and Hnrnph2 in mouse brain.

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Spatiotemporal expression of Hnrnph1 and Hnrnph2 in mouse brain.
(A) Num...
(A) Number of Hnrnph1 and Hnrnph2 copies normalized to Rpp30 in the cortices of indicated mice by ddRT-PCR. n = 3 for all groups. (B) Number of Hnrnph1 and Hnrnph2 copies normalized to Rpp30 in the cortices of WT C67BL/6J mice across prenatal and postnatal developmental time points by ddRT-PCR. n = 3 for all groups. (C) H scores for Hnrnph1 and Hnrnph2 probes in the brains of WT C67BL/6J mice across developmental time points by Halo analysis of BaseScope ISH. n = 3 for all groups. (D) Regional expression of Hnrnph1 and Hnrnph2 across the adult (P56) mouse brain by BaseScope ISH. White arrowheads indicate corpus callosum; asterisks indicate fiber tracts. Ob, olfactory bulb; CC, corpus callosum; IC, cerebral cortex/isocortex; H/DG, hippocampus/dentate gyrus; St, bed of nuclei of the stria terminalis; P, pons; M, medulla; Th, thalamus; Mb, rostral collicular midbrain; Cb, cerebellum; Cbc, cerebellar cortex; wmft, white matter fiber tracts. (E) Expression of Hnrnph1 and Hnrnph2 in major classes of brain cells at P7 by RNA. Data extracted from Brain RNA-Seq (46, 47). FPKM, fragments per kilobase of transcript per million mapped reads. (F) Top 5 expression cell clusters for Hnrnph1 and Hnrnph2 in adult mouse brain by single-cell RNA-Seq (48). Data are shown as the mean ± SEM for A–C and mean ± SD for E. **P < 0.01, ****P < 0.0001 by 2-way ANOVA with Šidák’s post test; #P < 0.05, ##P < 0.01, ####P < 0.0001 by 2-way ANOVA with Tukey’s post test. Where applicable, exact P values are provided in Supplemental Table 4.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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