In the News

Jepsen WM et al. Two additional males with X-linked, syndromic mental retardation carry de novo mutations in HNRNPH2. Clin Genet. 2019 Jun 24. doi:10.1111/cge.13580

Abstract

This letter is intended to directly respond to and complement that submitted by Harmsen et al in which they describe a male with mental retardation, X‐linked, syndromic, Bain‐type (MRXSB) due to a de novo hemizygous mutation in HNRNPH2 (c.617G>A, p.Arg206Gln) previously identified in females by Bain et al and presumed to be embryonically lethal in males.

We have identified two additional males with similar phenotypes carrying de novo mutations in HNRNPH2. Patient A is hemizygous for a second MRXSB mutation originally identified by Bain et al in three females within the nuclear localization sequence of HNRNPH2 (c.616C>T, p.Arg206Trp) serving as conclusive evidence that known MRXSB mutations are not embryonically lethal in males. Patient B is hemizygous for a private mutation in the second RNA recognition motif (RRM2) of HNRNPH2 (c.340C>T, p.Arg114Trp), suggesting that other mutations within this gene are capable of producing a range of similar phenotypes.

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Harmsen S et al. Bain type of X-linked syndromic mental retardation in boys. Clin Genet. 2019 Mar 18. doi: 10.1111/cge.13524.

Abstract

A hemizygous variant in the HNRNPH2 gene causes MRXSB in a male individual.

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Ruan QT et al. Changes in neuronal immunofluorescence in the C-versus N-terminal domains of hnRNP H following D1 dopamine receptor activiation. Neurosci Lett. 2018. doi:https://doi.org/10.1101/305565

Abstract

RNA binding proteins are a diverse class of proteins that regulate all aspects of RNA metabolism. Accumulating studies indicate that heterogeneous nuclear ribonucleoproteins are associated with cellular adaptations in response to drugs of abuse. We recently mapped and validated heterogeneous nuclear ribonucleoprotein H1 (Hnrnph1) as a quantitative trait gene underlying differential behavioral sensitivity to methamphetamine. The molecular mechanisms by which hnRNP H1 alters methamphetamine behaviors are unknown but could involve pre- and/or post-synaptic changes in protein localization and function. Methamphetamine initiates post-synaptic D1 dopamine receptor signaling indirectly by binding to pre-synaptic dopamine transporters and vesicular monoamine transporters of midbrain dopaminergic neurons which triggers revers e transport and accumulation of dopamine at the synapse. Here, we examined changes in neuronal localization of hnRNP H in primary rat cortical neurons that express dopamine receptors that can be modulated by the D1 or D2 dopamine receptor agonists SKF38393 and (-)-Quinpirole HCl, respectively. Basal immunostaining of hnRNP H was localized primarily to the nucleus. D1 dopamine receptor activation induced an increase in hnRNP H nuclear immunostaining as detected by immunocytochemistry with a C-domain directed antibody containing epitope near the glycine-rich domain but not with an N-domain specific antibody. Although there was no change in hnRNP H protein in the nucleus or cytoplasm, there was a decrease in Hnrnph1 transcript following D1 receptor stimulation. Taken together, these results suggest that D1 receptor activation increases availability of the hnRNP H C-terminal epitope, which could potentially reflect changes in protein-protein interactions. Thus, D1 receptor signaling could represent a key molecular post-synaptic event linking Hnrnph1 polymorphisms to drug-induced behavior.

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Pilch J et al. Evidence for HNRNPH1 being another gene for Bain type syndromic mental retardation. Clin Genet. 2018 Jun 25. doi: 10.1111/cge.13410

Abstract

The HNRNPH2-associated disease (mental retardation, X-linked, syndromic, Bain type [MRXSB, MIM #300986]) is caused by de novo mutations in the X-linked HNRNPH2 gene. MRXSB has been described in six female patients with dysmorphy, developmental delay, intellectual disability, autism, hypotonia and seizures. The reported HNRNPH2 mutations were clustered in the small domain encoding nuclear localization signal; in particular, the p.Arg206Trp was found in four independent de novo events. HNRNPH1 is a conserved autosomal paralogue of HNRNPH2 with a similar function in regulation of pre-mRNAs splicing but so far it has not been associated with human disease. We describe a boy with a disease similar to MRXSB in whom a novel de novo mutation c.616C>T (p.Arg206Trp) in HNRNPH1 was found (ie, the exact paralogue of the recurrent HNRNPH2 mutation). We propose that defective function of HNRNPH2 and HNRNPH1 nuclear localization signal has similar clinical consequences. An important difference between the two diseases is that the HNRNPH1-associated syndrome may occur in boys (as in the case of our proband) which is well explained by the autosomal (chr5q35.3) rather than X-linked localization of the HNRNPH2 gene.

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