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

Area of Science:

• Genetics
• Molecular Biology
• Developmental Biology

Background:

• GPKOW, an X-chromosome gene, encodes a nuclear RNA-binding protein involved in messenger RNA (mRNA) processing as a spliceosome subunit.
• Understanding the role of GPKOW in human health is crucial given its function in essential cellular processes.

Purpose of the Study:

• To establish GPKOW as a gene associated with human disease.
• To investigate the clinical manifestations and molecular mechanisms of GPKOW-related disorders.

Main Methods:

• Described three males from two families with hemizygous frameshift variants in the last exon of GPKOW.
• Evaluated the effect of a specific variant on gene expression in patient fibroblasts.
• Conducted in vivo studies using Drosophila melanogaster to assess the function of the GPKOW ortholog.

Main Results:

• Clinical presentations included intrauterine growth restriction, microcephaly, and abnormalities of the eyes, brain, skin, and skeleton.
• Fibroblast studies indicated reduced GPKOW protein levels, suggesting protein instability despite mRNA escaping nonsense-mediated decay.
• Drosophila studies revealed Gpkow is essential, dosage-sensitive, and enriched in neurons, with a truncated variant acting as a partial loss-of-function allele.

Conclusions:

• Rare variants in GPKOW are responsible for a multisystemic X-linked syndrome.
• GPKOW is a dosage-sensitive gene critical for normal development, particularly in the nervous system.