A disease‐causing variant in <scp><i>HNRNPH2</i></scp> inherited from an unaffected mother with skewed X‐inactivation

White-Brown, Alexandre; Lemire, Gabrielle; Itō, Yoko; Thornburg, Olivia; Bain, Jennifer; Dyment, David A.

doi:10.1002/ajmg.a.62549

Cited by 5 publications

(6 citation statements)

References 12 publications

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“…De novo pathogenic variants in HNRNPH2 were identified in 2016 in six unrelated individuals as a novel cause of an X-linked neurodevelopmental disorder whose features include developmental delay, intellectual disability, autism spectrum disorder, tone abnormalities, and seizure (OMIM 300986) (1). Since the initial identification of these mutations, the genotypic and phenotypic spectrum of the disorder has been expanded to include more than 30 individuals with 11 distinct de novo variants (2), as well as several maternally inherited cases (3)(4)(5). Although all six individuals in the initial report were female, subsequent studies have identified males carrying missense mutations in HNRNPH2 associated with a range of overlapping phenotypes (5)(6)(7).…”

Section: Introductionmentioning

confidence: 99%

A murine model of hnRNPH2-related neurodevelopmental disorder recapitulates clinical features of human disease and reveals a mechanism for genetic compensation ofHNRNPH2

Korff

Yang

O’Donovan

et al. 2022

Preprint

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Mutations in HNRNPH2 cause an X-linked neurodevelopmental disorder with a phenotypic spectrum that includes developmental delay, intellectual disability, language impairment, motor function deficits, and seizures. More than 90% of patients with this disorder have a missense mutation within or adjacent to the nuclear localization signal (NLS) of hnRNPH2, although the specific pathogenic consequences of these mutations have not been examined. Here we found that hnRNPH2 NLS mutations result in reduced interaction with the nuclear transport receptor Kapβ2 in vitro and in cultured human cells. These mutations also cause modest accumulation of hnRNPH2 in the cytoplasm, suggesting that mislocalization of the protein might contribute to pathogenesis. We generated two knock-in mouse models with human-equivalent mutations in the endogenous mouse gene Hnrnph2, as well as Hnrnph2 knockout (KO) mice, and subjected them to extensive, deep phenotyping. Mutant knock-in mice displayed a spectrum of phenotypes that recapitulated aspects of the human disorder, including reduced survival in males, craniofacial abnormalities, impaired motor functions, and increased susceptibility to audiogenic seizures. Mutant knock-in male mice developed more severe phenotypes than female mice, likely due to differences in X-chromosome gene dosage. In contrast, two independent lines of Hnrnph2 KO mice showed no detectable phenotypes. Notably, KO mice had upregulated expression of Hnrnph1, a close paralog of Hnrnph2, whereas mutant Hnrnph2 knock-in mice failed to upregulate Hnrnph1. Thus, genetic compensation by Hnrnph1 might be sufficient to counteract the loss of hnRNPH2. These findings suggest that the pathogenesis of HNRNPH2-related disorder in humans may be driven by a toxic gain of function or a complex loss of -HNRNPH2 function with impaired compensation by HNRNPH1. The carefully phenotyped mutant knock-in mice described here are an important resource for preclinical studies to assess the potential benefit of either gene replacement or therapeutic knockdown of mutant hnRNPH2.

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Section: Introductionmentioning

confidence: 99%

A murine model of hnRNPH2-related neurodevelopmental disorder recapitulates clinical features of human disease and reveals a mechanism for genetic compensation ofHNRNPH2

Korff

Yang

O’Donovan

et al. 2022

Preprint

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“…The sixth case alters the HNRNPH2 amino acid 209 from proline to leucine-p.P209L. Since the publication of this study, multiple reports have documented additional cases of de novo pathogenic HNRNPH2 variants present in individuals with similar clinical phenotypes (Bain et al, 2021;Gillentine et al, 2021;Harmsen et al, 2019;Jepsen et al, 2019;Kreienkamp et al, 2022;Peron et al, 2020;Somashekar et al, 2020;White-Brown et al, 2021). Termed Bain-type X-linked Intellectual Development Disorder (MRXSB; OMIM no.…”

Section: Neurodevelopmental Disease-associated Sequence Changes In Hn...mentioning

confidence: 93%

“…The distribution of changes in the HNRNPH2 sequence is striking, with most altered nucleotides within the conserved region encoding the putative nls (Van Dusen et al, 2010) and the beginning of the GYR region between qRRM2 and qRRM3 (Figure 6a). Specifically, multiple reports have confirmed and extended the initial study by Bain et al to show the presence of de novo heterozygous mutations in females and hemizygous mutations in males affecting nucleotides 616, 617, 626, 629, 634, 635, or 638 of HNRNPH2 (c.616C>T, p.R206W or c616C>G, p.R206G; c.617G>A, p.R206Q or c617G>T, p.R206L; c626C>T, p.P209L; c629A>G p.Y210C; c634A>G, p.R212G; c635G>C p.R212T; c638C>T p.P213L; Bain et al, 2021;Gillentine et al, 2021;Harmsen et al, 2019;Jepsen et al, 2019;Peron et al, 2020;Somashekar et al, 2020;White-Brown et al, 2021). Though rarer, reports of de novo mutations predicted to alter the HNRNPH2 qRRM domains include the following: qRRM1-c85C>T, p.R29C, qRRM2-c340C>T, p.R114W, and c422T>A, p.M141K, or qRRM3 c1019A>T, p.D340V (Bain et al, 2021;Jepsen et al, 2019;Kreienkamp et al, 2022).…”

Section: Neurodevelopmental Disease-associated Sequence Changes In Hn...mentioning

confidence: 99%

“…Mutations in HNRNPF/H genes and neurodevelopment disorders. Schematics of (a) HNRNPH2, (b) HNRNPH1, (c) HNRNPF, and (d) HNRNPH3 proteins indicating the locations of amino acid changes predicted based on mutations identified in individuals diagnosed with a neurodevelopmental disorder and reported in the following studies: Bain et al, 2016, 2021; Epi et al, 2013; Gillentine et al, 2021; Harmsen et al, 2019; Jepsen et al, 2019; Kreienkamp et al, 2022; Peron et al, 2020; Pilch et al, 2018; Reichert et al, 2020; Somashekar et al, 2020; White‐Brown et al, 2021. Figure panels created with BioRender.com.…”

Section: The Hnrnpf/h Rna Binding Proteins and Other Disease Statesmentioning

confidence: 99%

“…An earlier study also suggested that maternal germline mosaicism explains the inheritance of the c.616C>T p.R206W mutation by siblings (one male, one female; Somashekar et al, 2020), though the authors did not confirm this assertion experimentally. However, a study by White‐Brown et al showed inheritance of the same mutation c616C>T, p.R206W from an affected individual's biological mother, though she exhibited no symptoms because of skewed X‐chromosome inactivation (by a ratio of 1:99) of the disease‐causing allele (White‐Brown et al, 2021).…”

Section: The Hnrnpf/h Rna Binding Proteins and Other Disease Statesmentioning

confidence: 99%

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The HNRNPF/H RNA binding proteins and disease

Brownmiller

Caplen

2023

WIREs RNA

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The members of the HNRNPF/H family of heterogeneous nuclear RNA proteins—HNRNPF, HNRNPH1, HNRNPH2, HNRNPH3, and GRSF1, are critical regulators of RNA maturation. Documented functions of these proteins include regulating splicing, particularly alternative splicing, 5′ capping and 3′ polyadenylation of RNAs, and RNA export. The assignment of these proteins to the HNRNPF/H protein family members relates to differences in the amino acid composition of their RNA recognition motifs, which differ from those of other RNA binding proteins (RBPs). HNRNPF/H proteins typically bind RNA sequences enriched with guanine (G) residues, including sequences that, in the presence of a cation, have the potential to form higher‐order G‐quadruplex structures. The need to further investigate members of the HNRNPF/H family of RBPs has intensified with the recent descriptions of their involvement in several disease states, including the pediatric tumor Ewing sarcoma and the hematological malignancy mantle cell lymphoma; newly described groups of developmental syndromes; and neuronal‐related disorders, including addictive behavior. Here, to foster the study of the HNRNPF/H family of RBPs, we discuss features of the genes encoding these proteins, their structures and functions, and emerging contributions to disease.This article is categorized under: RNA in Disease and Development > RNA in Disease RNA Processing > Splicing Regulation/Alternative Splicing RNA Interactions with Proteins and Other Molecules > Protein–RNA Interactions: Functional Implications

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An expansion of the phenotype in individuals with SYNCRIP-Related Neurodevelopmental Disorder

Shafiq,

Feng,

Phillips

et al. 2024

Rare

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A disease‐causing variant in HNRNPH2 inherited from an unaffected mother with skewed X‐inactivation

Cited by 5 publications

References 12 publications

A murine model of hnRNPH2-related neurodevelopmental disorder recapitulates clinical features of human disease and reveals a mechanism for genetic compensation ofHNRNPH2

A murine model of hnRNPH2-related neurodevelopmental disorder recapitulates clinical features of human disease and reveals a mechanism for genetic compensation ofHNRNPH2

The HNRNPF/H RNA binding proteins and disease

An expansion of the phenotype in individuals with SYNCRIP-Related Neurodevelopmental Disorder

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