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| Microcephaly v1.310 | GPKOW | Zornitza Stark Marked gene: GPKOW as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Microcephaly v1.310 | GPKOW | Zornitza Stark Gene: gpkow has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Microcephaly v1.310 | GPKOW | Zornitza Stark Phenotypes for gene: GPKOW were changed from microcephaly MONDO:0001149; fetal growth restriction MONDO:0005030 to syndromic disease, MONDO:0002254, GPKOW-related | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Microcephaly v1.309 | GPKOW | Chirag Patel Classified gene: GPKOW as Green List (high evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Microcephaly v1.309 | GPKOW | Chirag Patel Gene: gpkow has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Microcephaly v1.308 | GPKOW |
Chirag Patel gene: GPKOW was added gene: GPKOW was added to Microcephaly. Sources: Literature Mode of inheritance for gene: GPKOW was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) Publications for gene: GPKOW were set to PMID: 40221893, 28612833 Phenotypes for gene: GPKOW were set to microcephaly MONDO:0001149; fetal growth restriction MONDO:0005030 Review for gene: GPKOW was set to GREEN Added comment: GPKOW, a gene on the X-chromosome, encodes a nuclear RNA-binding protein important in mRNA processing as a spliceosome subunit. It has been shown in numerous model organisms and in human cells to be essential for survival. PMID: 40221893 2 unrelated families with 3 affected males (deceased) presenting with IUGR, microcephaly, congenital ichthyosis, eye anomalies (microphthalmia, coloboma, ON hypoplasia), brain anomalies (absent septum pellucidum, ventriculomegaly), and skeletal anomalies (platyspondyly, brachydactyly). Trio WES/WGS testing identified 2 hemizygous frameshift variants affecting the last exon of GPKOW [p.(Arg441SerfsTer30) and p.(Ser444GlufsTer28)]. Some heterozygote females presented with short stature, microcephaly, and vision problems. Sequencing of fibroblasts' mRNA showed that GPKOW mRNA escapes nonsense-mediated decay but protein expression is reduced, suggesting protein instability. Studies in Drosophila showed that Gpkow is broadly expressed and 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. 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. PMID: 28612833 1 family with 5 affected males (stillbirth/TOP) with severe microcephaly and intrauterine growth restriction. X-exome sequencing in an obligate carrier identified a potential splice variant in the GPKOW gene (c.331+5G>A). The variant segregated in 9 additional family members, including one affected male fetus. GPKOW transcripts, in lymphoblastoid cell lines of 3 carrier females, showed that the variant disrupts normal splicing of its pre-mRNAs. A clonal culture expressing only the c.331+5G>A allele isolated from one carrier female LCL, showed an 80% reduction in wild type GPKOW mRNA, 70% reduction in the full length GPKOW protein and the presence of a truncated GPKOW protein with possible dominant negative effect. Sources: Literature |
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