C-Terminal Frameshift Variants in Gpkow Are Associated With a Multisystemic X-Linked Disorder

Authors

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
Shinya Yamamoto
Keren Machol

Language

English

Publication Date

7-1-2025

Journal

Genetics in Medicine

DOI

10.1016/j.gim.2025.101429

PMID

40221893

PMCID

PMC12435177

PubMedCentral® Posted Date

9-16-2025

PubMedCentral® Full Text Version

Author MSS

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.

Keywords

Humans, Animals, Frameshift Mutation, Male, Female, Drosophila melanogaster, Pedigree, Genetic Diseases, X-Linked, RNA-Binding Proteins, Microcephaly, Child, Phenotype, Fibroblasts, Drosophila Proteins

Published Open-Access

yes

Recommended Citation

Mok, Jung-Wan; Mackay, Laura; Blazo, Maria; et al., "C-Terminal Frameshift Variants in Gpkow Are Associated With a Multisystemic X-Linked Disorder" (2025). Duncan NRI Faculty and Staff Publications. 138.
https://digitalcommons.library.tmc.edu/duncar_nri_pub/138