Mok Jung-Wan, Mackay Laura, Blazo Maria, Mizerik Elizabeth, Gecz Jozef, Carroll Renee, Nizon Mathilde, Rondeau Sophie, Joubert Madeleine, Cuinat Silvestre, Deb Wallid, Valle Sirias Fernanda, Weisz-Hubshman Monika, Ketkar Shamika, Polak Urszula, Tran Alyssa A, Kearney Debra, Hanchard Neil A, Kanca Oguz, Wangler Michael F, Bellen Hugo J, Lee Brendan H, Yamamoto Shinya, Machol Keren
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX.
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX; Genetics Department, Texas Children's Hospital, Houston, TX.
Genet Med. 2025 Jul;27(7):101429. doi: 10.1016/j.gim.2025.101429. Epub 2025 Apr 10.
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.
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.
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.
Rare variants in GPKOW cause a multisystemic X-linked syndrome.
GPKOW是位于X染色体上的一个基因，编码一种核RNA结合蛋白，作为剪接体亚基在信使核糖核酸（mRNA）加工过程中起重要作用。本研究旨在确定GPKOW为一种疾病相关基因。
我们描述了来自2个不相关家族的3名男性，他们存在影响GPKOW最后一个外显子的半合子移码变异，分别为p.(Arg441SerfsTer30)和p.(Ser444GlufsTer28)。在患者成纤维细胞中评估了p.(Ser444GlufsTer28)对基因表达的影响。针对果蝇中唯一的GPKOW直系同源基因CG10324（Gpkow）进行了体内研究。
临床表现包括宫内生长受限、小头畸形/小脑畸形，以及眼睛、大脑、皮肤和骨骼异常。杂合子女性表现为身材矮小、小头畸形和视力问题。成纤维细胞mRNA测序证实GPKOW mRNA逃避了无义介导的衰变。然而，蛋白质水平降低表明蛋白质不稳定。果蝇研究表明，Gpkow是必需的且广泛表达。它在发育中和成年果蝇的眼睛和头部的神经元和神经胶质细胞中富集。在果蝇眼睛中敲低和过表达Gpkow会导致无眼/无头表型，表明该基因对剂量敏感。重要的是，p.(Ser444GlufsTer28)变异体的过表达导致的缺陷比参考等位基因轻，表明截短的蛋白质表现为部分功能丧失等位基因。
GPKOW中的罕见变异导致一种多系统X连锁综合征。
