C-terminal frameshift variants in GPKOW are associated with a multisystemic X-linked disorder
Date
2025
Authors
Mok, J.W.
Mackay, L.
Blazo, M.
Mizerik, E.
Gecz, J.
Carroll, R.
Nizon, M.
Rondeau, S.
Joubert, M.
Cuinat, S.
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Journal article
Citation
Genetics in Medicine, 2025; 27(7):101429-101429
Statement of Responsibility
Jung-Wan Mok, Laura Mackay, Maria Blazo, Elizabeth Mizerik, Jozef Gecz, Renee Carroll, Mathilde Nizon, Sophie Rondeau, Madeleine Joubert, Silvestre Cuinat, Wallid Deb, Fernanda Valle Sirias, Monika Weisz-Hubshman, Shamika Ketkar, Urszula Polak, Alyssa A. Tran, Debra Kearney, Neil A. Hanchard, Oguz Kanca, Michael F. Wangler, Hugo J. Bellen, Brendan H. Lee, Baylor College of Medicine Center for Precision Medicine Models, Shinya Yamamoto, Keren Machol
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Abstract
Purpose: GPKOW, a gene on the X-chromosome, encodes a nuclear RNA-binding protein important in messenger RNA (mRNA) processing as a spliceosome subunit. This work aims to establish GPKOW as a disease-associated gene. Methods: We describe 3 males from 2 unrelated families with hemizygous frameshift variants affecting the last exon of GPKOW p.(Arg441SerfsTer30) and p.(Ser444GlufsTer28). The effect of p.(Ser444GlufsTer28) on gene expression was evaluated in patient’s fibroblasts. In vivo studies in Drosophila melanogaster targeting the sole GPKOW fly ortholog, CG10324 (Gpkow) were performed. Results: Clinical presentations included intrauterine growth restriction, microcephaly/microencephaly, and eye, brain, skin, and skeletal abnormalities. Heterozygote females presented with short stature, microcephaly, and vision problems. Sequencing of fibroblasts’ mRNA confirmed that GPKOW mRNA escapes nonsense-mediated decay. Yet, reduced protein levels suggested protein instability. Studies in Drosophila showed that Gpkow is essential and broadly expressed. It is enriched in neurons and glia in eyes and head of developing and adult flies. Knockdown and overexpression of Gpkow in the fly eye cause eyeless/headless phenotype, suggesting that the gene is dosage sensitive. Importantly, overexpression of the p.(Ser444GlufsTer28) variant caused milder defects than the reference allele, indicating that the truncated protein behaves as a partial loss-of-function allele. Conclusion: Rare variants in GPKOW cause a multisystemic X-linked syndrome.
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© 2025 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.