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Pathogenic ZNF319 variant disrupts nuclear localization and transcriptional regulation to cause a novel form of autosomal recessive leukodystrophy

Journal of Human Genetics volume 70, pages 577–587 (2025)Cite this article

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Abstract

Leukodystrophies are inherited disorders characterized by progressive degeneration of white matter in the central nervous system. Here, we investigate a previously uncharacterized autosomal recessive leukodystrophy which is associated with the homozygous missense variant in ZNF319 (c.800T>C; p.Phe267Ser) in an 18-year-old male presenting with spasticity, ataxia, cognitive decline, and white matter abnormalities on MRI. The variant was absent in population databases (gnomAD, ClinVar) and predicted to be pathogenic by multiple in silico tools. Molecular dynamics simulations revealed that F267 is a stabilizing residue within a β-strand of the zinc finger domain, forming π-stacking and hydrophobic interactions that are lost upon substitution with serine, leading to structural instability, increased flexibility, and protein unfolding. Despite normal transcript and protein expression, ZNF319-F267S mislocalized to the cytoplasm due to disruption of its bipartite nuclear localization signal (NLS), resulting in impaired interaction with importin α1 (KPNA1). Functional analysis confirmed that the mutation disrupts nuclear transport and prevents transcriptional activation of genes involved in myelination. Protein interaction network and gene ontology analysis highlighted ZNF319’s role in transcriptional regulation and its localization in the CHOP-C/EBP transcriptional complex. Expression profiling demonstrated ZNF319 enrichment in oligodendrocytes and white matter regions, correlating with the observed leukoencephalopathy. Our study identifies ZNF319 as a novel gene implicated in human leukodystrophy and highlights how a single-point mutation can compromise nuclear import and transcriptional function, leading to white matter degeneration. These findings expand the genetic landscape of leukodystrophies and provide mechanistic insights into transcriptional regulation in myelin maintenance.

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The data generated or analyzed during this study are available from the corresponding author upon request.

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Acknowledgements

We sincerely thank the proband and his family for their participation and continued support for this study.

Funding

The authors extend their appreciation to the Deanship of Research and Graduate Studies at King Khalid University for funding this work through Large Research Project under grant number RGP2/257/45.

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Authors and Affiliations

  1. Hiralal Mazumdar Memorial College for Women, West Bengal State University, Kolkata, West Bengal, India

    S Rehan Ahmad

  2. Department of Basic Medical Science, College of Applied Medical Sciences, Khamis Mushait Campus, King Khalid University (KKU), Abha, Saudi Arabia

    Md. Zeyaullah

  3. Department of Public Health, College of Applied Medical Sciences, Khamis Mushait Campus, King Khalid University (KKU), Abha, Saudi Arabia

    Yousef Zahrani, Abdelrhman A. G. Altijani & Adam Dawria

  4. Department of Public Health, College of Health Sciences, Saudi Electronic University, Dammam, Saudi Arabia

    Ahmed Salih

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  1. S Rehan Ahmad
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  2. Md. Zeyaullah
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Contributions

S Rehan Ahmad: Conceptualization, study design, experimental execution, data analysis, and manuscript writing. Md. Zeyaullah: Methodology and data analysis. Yousef Zahrani: Genetic counseling and contribution to manuscript preparation. Adam Dawria: Clinical evaluation, diagnosis, and genotype–phenotype interpretation. Abdelrhman AG Altijani: Methodology and data analysis. Ahmed Salih: Methodology and data analysis.

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Correspondence to S Rehan Ahmad.

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Ahmad, S.R., Zeyaullah, M., Zahrani, Y. et al. Pathogenic ZNF319 variant disrupts nuclear localization and transcriptional regulation to cause a novel form of autosomal recessive leukodystrophy. J Hum Genet 70, 577–587 (2025). https://doi.org/10.1038/s10038-025-01386-2

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