Disease-associated variants alter a novel physiological role of hnRNP H2 in neuronal development

Abstract

Heterogeneous nuclear ribonucleoprotein H2 (hnRNP H2) is a member of the hnRNP family of RNA-binding proteins that regulate neuronal function through multiple aspects of RNA metabolism. Mutations in the nuclear localisation signal (NLS) and quasi-RNA recognition motifs (qRRMs) of hnRNP H2 have recently been linked to a severe developmental syndrome, termed HNRNPH2-related neurodevelopmental disorder. Despite its emerging importance, the physiological roles of hnRNP H2 in neuronal development and synaptic maturation, and how disease-associated variants alter these processes to drive pathology, remain poorly understood. Here, we show that hnRNP H2 is expressed in hippocampal neurons and localises to the synaptic compartment. Knockdown of hnRNP H2 revealed essential roles of the protein in the regulation of neuronal morphology, dendritic spine maturation, synaptic transmission, and cortical neuronal migration in vivo. Disease-associated hnRNP H2 variants altered protein localisation and activity-dependent synaptic recruitment, resulting in defects in neuronal morphology, in vivo cortical neuronal migration and laminar orientation, dendritic spine maturation, and synaptic function. Together, these findings establish hnRNP H2 as a critical regulator of neurodevelopment and identify a molecular basis for HNRNPH2-related neurodevelopmental disorder.

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BibTeX RIS

BibTeX

@misc{lourinho2026diseaseassociated,
  title = {{Disease-associated variants alter a novel physiological role of hnRNP H2 in neuronal development}},
  author = {A. Lourinho and M. S. Silva and E. Tahiri and M. D'Ambrosio and A. D. Pinto and S. Calvo Parra and G. De Pietro and G. Galvao and A. B. Caniceiro and L. Pereira de Almeida and P. Pinheiro and I. S. Moreira and R. J. Nobre and M. Mele and A. W. Cwetsch and C. B. Duarte and R. O. Costa},
  howpublished = {bioRxiv},
  year = {2026},
  month = oct,
  doi = {10.64898/2026.10.02.756225},
  url = {https://www.biorxiv.org/content/10.64898/2026.10.02.756225v1},
  note = {CC BY-NC-ND},
}

RIS

TY  - UNPB
TI  - Disease-associated variants alter a novel physiological role of hnRNP H2 in neuronal development
AU  - A. Lourinho
AU  - M. S. Silva
AU  - E. Tahiri
AU  - M. D'Ambrosio
AU  - A. D. Pinto
AU  - S. Calvo Parra
AU  - G. De Pietro
AU  - G. Galvao
AU  - A. B. Caniceiro
AU  - L. Pereira de Almeida
AU  - P. Pinheiro
AU  - I. S. Moreira
AU  - R. J. Nobre
AU  - M. Mele
AU  - A. W. Cwetsch
AU  - C. B. Duarte
AU  - R. O. Costa
PY  - 2026
DA  - 2026/10/02
PB  - bioRxiv
DO  - 10.64898/2026.10.02.756225
UR  - https://www.biorxiv.org/content/10.64898/2026.10.02.756225v1
AB  - Heterogeneous nuclear ribonucleoprotein H2 (hnRNP H2) is a member of the hnRNP family of RNA-binding proteins that regulate neuronal function through multiple aspects of RNA metabolism. Mutations in the nuclear localisation signal (NLS) and quasi-RNA recognition motifs (qRRMs) of hnRNP H2 have recently been linked to a severe developmental syndrome, termed HNRNPH2-related neurodevelopmental disorder. Despite its emerging importance, the physiological roles of hnRNP H2 in neuronal development and synaptic maturation, and how disease-associated variants alter these processes to drive pathology, remain poorly understood. Here, we show that hnRNP H2 is expressed in hippocampal neurons and localises to the synaptic compartment. Knockdown of hnRNP H2 revealed essential roles of the protein in the regulation of neuronal morphology, dendritic spine maturation, synaptic transmission, and cortical neuronal migration in vivo. Disease-associated hnRNP H2 variants altered protein localisation and activity-dependent synaptic recruitment, resulting in defects in neuronal morphology, in vivo cortical neuronal migration and laminar orientation, dendritic spine maturation, and synaptic function. Together, these findings establish hnRNP H2 as a critical regulator of neurodevelopment and identify a molecular basis for HNRNPH2-related neurodevelopmental disorder.
ER  -

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