Rare variants in GPKOW associated with multisystemic X-linked developmental disorder microbiologystudy

A new study published in Genetics in Medicine identifies a novel disease-associated gene, GPKOW, that plays an important role in the development of the brain, eyes and other organ systems. Researchers at Baylor College of Medicine, the Jan and Dan Duncan Neurological Research Institute (Duncan NRI) at Texas Children’s Hospital and collaborating institutions show that rare variants in GPKOW, a gene on the X-chromosome, cause a severe multisystemic syndrome resulting in restricted fetal growth, small head size (microcephaly) and severe brain and eye abnormalities.

Whole-exome sequencing, which analyzes the protein-coding regions of the genome, was conducted for patients and their parents. The results showed rare variants in a similar area on GPKOW, a gene that encodes a protein important to mRNA processing that previously has not been well studied. Baylor researchers at the Center for Precision Medicine Models performed functional gene studies in Drosophila (fruit fly) models to determine if these variants in GPKOW were the cause of the disease.

“We found that the fly ortholog of GPKOW is critically important to survival in the fly,” said first author Dr. Jung-Wan Mok, postdoctoral associate in Dr. Shinya Yamamoto’s lab at Baylor. “Downregulation of this gene in specific tissues like the eyes or brain that are affected in the patients causes severe phenotypes and problems in the developmental process in the fly model.”

Mok and his colleagues also showed that the GPKOW variant is a partial loss-of-function allele, which means that gene function is downregulated, but not turned off. Because the gene is located on the X chromosome, males with only one copy of this gene experience severe phenotypes.

Unfortunately, two male patients in the study, maternal half-brothers, passed away within the first year of life. Females with one normal copy of the gene have less severe phenotypes, presenting with short stature, microcephaly and vision problems.

“Characterization of this gene function and the spectrum of conditions that it may cause will help clinicians to provide targeted clinical management for the patients and will push research on this condition even further,” said co-corresponding author Dr. Keren Machol, assistant professor of molecular and human genetics at Baylor.

“The documentation of GPKOW as a human disease-causing gene will help identify other individuals affected by this understudied condition, ending diagnostic odysseys for many families and promoting further research,” said co-corresponding author Dr. Shinya Yamamoto, associate professor of molecular and human genetics and neuroscience at Baylor and investigator at the Duncan NRI.