C-terminal frameshift variants in GPKOW are associated with a multisystemic X-linked disorder

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dc.contributor.authorMok, J.W.
dc.contributor.authorMackay, L.
dc.contributor.authorBlazo, M.
dc.contributor.authorMizerik, E.
dc.contributor.authorGecz, J.
dc.contributor.authorCarroll, R.
dc.contributor.authorNizon, M.
dc.contributor.authorRondeau, S.
dc.contributor.authorJoubert, M.
dc.contributor.authorCuinat, S.
dc.contributor.authorDeb, W.
dc.contributor.authorValle Sirias, F.
dc.contributor.authorWeisz-Hubshman, M.
dc.contributor.authorKetkar, S.
dc.contributor.authorPolak, U.
dc.contributor.authorTran, A.A.
dc.contributor.authorKearney, D.
dc.contributor.authorHanchard, N.A.
dc.contributor.authorKanca, O.
dc.contributor.authorWangler, M.F.
dc.contributor.authoret al.
dc.date.issued2025
dc.description.abstractPurpose: 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.
dc.description.statementofresponsibilityJung-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
dc.identifier.citationGenetics in Medicine, 2025; 27(7):101429-101429
dc.identifier.doi10.1016/j.gim.2025.101429
dc.identifier.issn1098-3600
dc.identifier.issn1530-0366
dc.identifier.orcidGecz, J. [0000-0002-7884-6861]
dc.identifier.orcidCarroll, R. [0000-0002-6979-3710]
dc.identifier.urihttps://hdl.handle.net/2440/147604
dc.language.isoen
dc.publisherElsevier
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1155224
dc.rights© 2025 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.
dc.source.urihttps://doi.org/10.1016/j.gim.2025.101429
dc.subjectCG10324; Drosophila melanogaster; GPKOW; Minor Spliceosome; Neurodevelopment
dc.subject.meshFibroblasts
dc.subject.meshAnimals
dc.subject.meshHumans
dc.subject.meshDrosophila melanogaster
dc.subject.meshMicrocephaly
dc.subject.meshGenetic Diseases, X-Linked
dc.subject.meshRNA-Binding Proteins
dc.subject.meshDrosophila Proteins
dc.subject.meshPedigree
dc.subject.meshPhenotype
dc.subject.meshFrameshift Mutation
dc.subject.meshChild
dc.subject.meshFemale
dc.subject.meshMale
dc.titleC-terminal frameshift variants in GPKOW are associated with a multisystemic X-linked disorder
dc.typeJournal article
pubs.publication-statusPublished

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