<i>HNRNPH2</i> variant linked to intellectual disability disrupts myelination by impairing oligodendrocyte differentiation

Yang Jiao; Xingyu Pan; Jingrong Zhao; Xiaoyu Teng; Xiaoyi Liao; Xinyu Hu; Qiu Wang; Dandan Zheng; Yuxiang Pan; Xiaohui Deng; Xinyi Tan; Yun Stone Shi; Xu Zhang; Lan Bao; Bin Wang

doi:10.1016/j.jgg.2025.12.006

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HNRNPH2 variant linked to intellectual disability disrupts myelination by impairing oligodendrocyte differentiation

doi: 10.1016/j.jgg.2025.12.006

a. Guangdong Institute of Intelligence Science and Technology, Hengqin, Zhuhai, Guangdong 519031, China;
b. Institute of Neuroscience and State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China;
c. Key Laboratory of Multi-cell Systems, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China;
d. School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China

Funds:

We thank Prof. Jingyi Hui (CAS Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences) for insightful guidance, Dr. Zhixiong Liu (Guangdong Institute of Intelligence Science and Technology) for technical assistance in the OPC culture, and the platform for structure and function of neural network in Guangdong Institute of Intelligence Science and Technology for providing technical support. This work was supported by grants from the National Natural Science Foundation of China (32471018, 32070967, and 32070968).

Received Date: 2025-12-02
Accepted Date: 2025-12-17
Rev Recd Date: 2025-12-17

Available Online: 2025-12-25

Abstract

Abstract

Intellectual disability (ID) arises from complex pathogenic mechanisms. Although myelin dysfunction and white matter damage have been implicated, the cellular and molecular mechanisms linking impaired myelination to cognitive deficits remain largely unknown. Here, we identify a de novo heterogeneous nuclear ribonucleoprotein H2 (HNRNPH2) variant, c.638C>T (p.Pro213Leu), in patients with ID. The Hnrnph2^P213L knock-in mice display spatial learning deficits, representing a partial phenotypic overlap with HNRNPH2-related neurodevelopmental disorder. Notably, Hnrnph2^P213L mice exhibit significant myelination defects, primarily due to the impaired differentiation of oligodendrocyte progenitor cells. Furthermore, the myelin-enhancing drug benztropine rescues myelination, restores myelin-related gene expression, and ameliorates cognitive deficits, highlighting the role of hnRNPH2 P213L-induced myelin abnormalities in the pathogenesis of ID. Mechanistically, the P213L mutation disrupts the interaction between hnRNPH2 and its target transcripts, leading to the downregulation of myelination-related genes. Collectively, these findings reveal a critical mechanistic connection between myelin dysfunction and ID, thereby offering potential therapeutic insights for X-linked neurodevelopmental disorders.
- HNRNPH2,
- RNA binding protein,
- Intellectual disability,
- Myelination,
- Oligodendrocyte differentiation

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References

Korff, A., Yang, X., O'Donovan, K., Gonzalez, A., Teubner, B.J., Nakamura, H., Messing, J., Yang, F., Carisey, A.F., Wang, Y.D., et al., 2023. A murine model of hnRNPH2-related neurodevelopmental disorder reveals a mechanism for genetic compensation by Hnrnph1. J. Clin. Invest. 133, e160309.

Bain, J.M., Thornburg, O., Pan, C., Rome-Martin, D., Boyle, L., Fan, X., Devinsky, O., Frye, R., Hamp, S., Keator, C.G., et al., 2021. Detailed clinical and psychological phenotype of the X-linked HNRNPH2-related neurodevelopmental disorder. Neurol. Genet. 7, e551.

Bittles, A.H., Petterson, B.A., Sullivan, S.G., Hussain, R., Glasson, E.J., Montgomery, P.D., 2002. The influence of intellectual disability on life expectancy. J. Gerontol. A. Biol. Sci. Med. Sci. 57, M470-472.

Bohlen, J.F., Cleary, C.M., Das, D., Sripathy, S.R., Sadowski, N., Shim, G., Kenney, R.F., Buchler, I.P., Banerji, T., Scanlan, T.S., et al., 2023. Promyelinating drugs promote functional recovery in an autism spectrum disorder mouse model of Pitt-Hopkins syndrome. Brain 146, 3331-3346.

Campos, A.C., Fogaca, M.V., Aguiar, D.C., Guimaraes, F.S., 2013. Animal models of anxiety disorders and stress. Braz. J. Psychiatry 35 Suppl 2, S101-S111.

Deshmukh, V.A., Tardif, V., Lyssiotis, C.A., Green, C.C., Kerman, B., Kim, H.J., Padmanabhan, K., Swoboda, J.G., Ahmad, I., Kondo, T., et al., 2013. A regenerative approach to the treatment of multiple sclerosis. Nature 502, 327-332.

Doll, C.A., Yergert, K.M., Appel, B.H., 2020. The RNA binding protein fragile X mental retardation protein promotes myelin sheath growth. Glia 68, 495-508.

Dominguez, C., Fisette, J.F., Chabot, B., Allain, F.H., 2010. Structural basis of G-tract recognition and encaging by hnRNP F quasi-RRMs. Nat. Struct. Mol. Biol. 17, 853-861.

Emery, B., Lu, Q.R., 2015. Transcriptional and epigenetic regulation of oligodendrocyte development and myelination in the central nervous system. Cold Spring Harb. Perspect. Biol. 7, a020461.

Fernandez-Enright, F., Andrews, J., 2016. Lingo-1: a novel target in therapy for Alzheimer's disease? Neural Regen. Res. 11, 88-89.

Filley, C.M., 2016. Fragile X tremor ataxia syndrome and white matter dementia. Clin. Neuropsychol. 30, 901-912.

Gonzalez, J.N., Goldman, S., Carter, M.T., Bain, J.M., 2023. Rett-like Phenotypes in HNRNPH2-related neurodevelopmental disorder. Genes (Basel) 14, 1154.

Grammatikakis, I., Zhang, P., Panda, A.C., Kim, J., Maudsley, S., Abdelmohsen, K., Yang, X., Martindale, J.L., Motino, O., Hutchison, E.R., et al., 2016. Alternative splicing of neuronal differentiation factor TRF2 regulated by HNRNPH1/H2. Cell Rep. 15, 926-934.

Hamed, S.A., Hadad, A.F.E., 2024. The effect of anticholinergic drugs on cognition of patients with Parkinson's disease: a cohort study from the Egyptian population. Expert Rev. Clin. Pharmacol. 17, 743-753.

Harmsen, S., Buchert, R., Mayatepek, E., Haack, T.B., Distelmaier, F., 2019. Bain type of X-linked syndromic mental retardation in boys. Clin. Genet. 95, 734-735.

Jepsen, W.M., Ramsey, K., Szelinger, S., Llaci, L., Balak, C., Belnap, N., Bilagody, C., De Both, M., Gupta, R., Naymik, M., et al., 2019. Two additional males with X-linked, syndromic mental retardation carry de novo mutations in HNRNPH2. Clin. Genet. 96,183-185.

Jiang, Y., Fu, X., Zhang, Y., Wang, S.-F., Zhu, H., Wang, W.-K., Zhang, L., Wu, P., Wong, C.C.L., Li, J., et al., 2021. Rett syndrome linked to defects in forming the MeCP2/Rbfox/LASR complex in mouse models. Nat. Commun. 12, 5767.

Kreienkamp, H.-J., Wagner, M., Weigand, H., McConkie-Rossell, A., McDonald, M., Keren, B., Mignot, C., Gauthier, J., Soucy, J.-F., Michaud, J.L., et al., 2021. Variant-specific effects define the phenotypic spectrum of HNRNPH2-associated neurodevelopmental disorders in males. Hum. Genet. 141, 257-272.

Kuhn, S., Gritti, L., Crooks, D., Dombrowski, Y., 2019. Oligodendrocytes in development, myelin generation and beyond. Cells. 12, 1424.

Liu, Z., Yan, M., Liang, Y., Liu, M., Zhang, K., Shao, D., Jiang, R., Li, L., Wang, C., Nussenzveig, D.R., et al., 2019. Nucleoporin Seh1 interacts with Olig2/Brd7 to promote oligodendrocyte differentiation and myelination. Neuron 102, 587-601.

Ma, X., Zhu, L., Chen, W., Sheng, M., Peng, F., Liang, M., Zhao, Y., Wang, Y., Feng, Z., 2021. Generation of an iPSC line (SMCPGi001-A) from a patient with Bain type X-linked mental retardation syndrome carrying HNRNPH2 gene mutation. Stem Cell Res. 57, 102571.

Madhok S, B.J., 2022. HNRNPH2-related neurodevelopmental disorder. GeneReviews® [Internet], University of Washington, Seattle.

Mandler, M.D., Ku, L., Feng, Y., 2014. A cytoplasmic quaking I isoform regulates the hnRNP F/H-dependent alternative splicing pathway in myelinating glia. Nucleic Acids Res. 42, 7319-7329.

Pan, X., Zhao, J., Zhou, Z., Chen, J., Yang, Z., Wu, Y., Bai, M., Jiao, Y., Yang, Y., Hu, X., et al., 2021. 5'-UTR SNP of FGF13 causes translational defect and intellectual disability. Elife 29, e63021.

Pereira, G.B., Dobretsova, A., Hamdan, H., Wight, P.A., 2011. Expression of myelin genes: comparative analysis of Oli-neu and N20.1 oligodendroglial cell lines.J. Neurosci. Res. 89, 1070-1078.

Porsolt, R.D., Brossard, G., Hautbois, C., Roux, S., 2001. Rodent models of depression: forced swimming and tail suspension behavioral despair tests in rats and mice. Curr. Protoc. Neurosci. Chapter 8, ns0810as14.

Rowland, M.E., Jiang, Y., Shafiq, S., Ghahramani, A., Pena-Ortiz, M.A., Dumeaux, V., Berube, N.G., 2023. Systemic and intrinsic functions of ATRX in glial cell fate and CNS myelination in male mice. Nat. Commun. 14, 7090.

Salazar, R., Beenders, S., LaMarca, N.M., Thornburg, O., Rubin-Thompson, L., Snow, A., Goldman, S., Chung, W.K., Bain, J.M., 2021. Cross-sectional, quantitative analysis of motor function in females with HNRNPH2-related disorder. Res. Dev. Disabil. 119, 104110.

Shankar, R., Wilcock, M., Oak, K., McGowan, P., Sheehan, R., 2019. Stopping, rationalising or optimising antipsychotic drug treatment in people with intellectual disability and/or autism. Drug Ther. Bull. 57, 10-13.

Shevell, M., 2008. Global developmental delay and mental retardation or intellectual disability: conceptualization, evaluation, and etiology. Pediatr. Clin. North Am. 55, 1071-1084.

Somashekar, P.H., Narayanan, D.L., Jagadeesh, S., Suresh, B., Vaishnavi, R.D., Bielas, S., Girisha, K.M., Shukla, A., 2019. Bain type of X-linked syndromic mental retardation in a male with a pathogenic variant in HNRNPH2. Am. J. Med. Genet. A 182, 183-188.

Stevenson, R.E., Procopio-Allen, A.M., Schroer, R.J., Collins, J.S., 2003. Genetic syndromes among individuals with mental retardation. Am. J. Med. Genet. A 123A, 29-32.

Stolt, C.C., Rehberg, S., Ader, M., Lommes, P., Riethmacher, D., Schachner, M., Bartsch, U., Wegner, M., 2002. Terminal differentiation of myelin-forming oligodendrocytes depends on the transcription factor Sox10.Genes Dev. 16, 165-170.

Swanson, M.R., Hazlett, H.C., 2019. White matter as a monitoring biomarker for neurodevelopmental disorder intervention studies. J. Neurodev. Disord. 11, 33.

Vorhees, C.V., Williams, M.T., 2006. Morris water maze: procedures for assessing spatial and related forms of learning and memory. Nat. Protoc. 1, 848-858.

White-Brown, A.M., Lemire, G., Ito, Y.A., Thornburg, O., Bain, J.M., Dyment, D.A., 2021. A disease-causing variant in HNRNPH2 inherited from an unaffected mother with skewed X-inactivation. Am. J. Med. Genet. A 188, 668-671.

Wong, M., 2019. The role of glia in epilepsy, intellectual disability, and other neurodevelopmental disorders in tuberous sclerosis complex. J. Neurodev. Disord. 11, 30.

Xing, Y., Wang, E., Aslanzadeh, V., Papa, F., Zhu, H., de la Grange, P., Cambi, F., 2012. Global profiling of alternative splicing events and gene expression regulated by hnRNPH/F. PLoS ONE 7, e51266.

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