HNRNPH2 – Bain type X-linked Syndromic Intellectual Disability

Heterogeneous nuclear ribonucleoprotein H2 (HNRNPH2) has been implicated in an X-linked syndromic intellectual disability known as Bain type (MONDO:0010512). Affected males present with global developmental delay, moderate-to-severe intellectual disability, autistic features, hypotonia, seizures and dysmorphic facial features. Disease-causing variants cluster within or adjacent to the proline-tyrosine nuclear localization signal (PY-NLS) of HNRNPH2, disrupting nuclear import and leading to downstream splicing defects.

Initial evidence came from a single male with de novo hemizygous missense variants c.617G>A (p.Arg206Gln) and c.616C>T (p.Arg206Trp) ([PMID:30887513]). A subsequent multi-patient study described eight additional unrelated male individuals, including monozygotic twins, harboring pathogenic missense, nonsense and frameshift variants—among them recurrent de novo p.Arg114Trp and p.Pro209Leu—demonstrating consistent de novo occurrence across nine probands ([PMID:34907471]). Variants are predominantly missense (5 distinct) within the NLS and quasi-RNA recognition motifs, with recurrent p.Arg206Trp observed in multiple families.

In vitro functional assays revealed that p.Arg206Gln and p.Pro209Leu variants cause aberrant cytoplasmic accumulation due to impaired nucleocytoplasmic shuttling, while p.Arg114Trp reduces interaction with the LASR splicing assembly. RNA-sequencing of patient fibroblasts with p.Arg114Trp showed widespread alternative splicing alterations, consistent with a spliceopathy ([PMID:34907471]). Cryo-EM of the HNRNPH2 PY-NLS bound to Karyopherin-β2 demonstrated that disease variants at epitopes 2–4 impair nuclear import by weakening transporter binding ([PMID:37279758]).

A knock-in mouse model carrying human-equivalent NLS mutations recapitulated key clinical features—reduced survival in males, motor and cognitive deficits, and seizure susceptibility—whereas Hnrnph2 knockout mice showed compensation by Hnrnph1 and lacked phenotype, supporting a toxic gain-of-function or complex loss-of-function mechanism ([PMID:37463454]).

Collectively, >9 unrelated de novo HNRNPH2 variants with robust functional concordance across cellular and animal models provide strong evidence for a gene-disease association. Future studies on natural history and therapeutic interventions are warranted. Key Take-home: HNRNPH2 pathogenic variants disrupt nuclear import and splicing leading to Bain type X-linked syndromic intellectual disability.

References

• Clinical genetics • 2019 • Bain type of X-linked syndromic mental retardation in boys. PMID:30887513
• Human genetics • 2022 • Variant-specific effects define the phenotypic spectrum of HNRNPH2-associated neurodevelopmental disorders in males. PMID:34907471
• Structure (London, England : 1993) • 2023 • A new Karyopherin-β2 binding PY-NLS epitope of HNRNPH2 linked to neurodevelopmental disorders PMID:37279758
• The Journal of clinical investigation • 2023 • A murine model of hnRNPH2-related neurodevelopmental disorder reveals a mechanism for genetic compensation by Hnrnph1 PMID:37463454

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