Published Online May 25, 2016

Finding a genetic mutation linked to cleft palate—one of the world’s most common birth defects—was just part of the story for this research project. How the team made the discovery was nearly as important as the discovery itself.

The paper, published online in May 2016, reveals that mutations in the Golgb1 gene can lead to cleft palate. Specifically, Golgb1 mutant mouse embryos exhibit increased cell density, reduced hyaluronan accumulation and impaired protein glycosylation during palate development.

Normally, embryonic palatal shelves initiate and grow vertically from the oral side of the maxilla and then elevate to the horizontal position above the tongue to fuse at the midline to form the roof of the oral cavity. However, in mice with the mutation, the palatal tissue proteins do not glycosylate properly. Palatal shelves remain in the vertical position and unable to bond. This results in cleft palate at birth.

Yu Lan, PhD, Plastic Surgery, and Rulang Jiang, PhD, Developmental Biology, collaborated on the study.

“Identification of the link between the Golgb1 gene and cleft palate was completely unexpected because Golgb1 is expressed in every cell, but the results reveal that Golgb1 has specific functions in protein glycosylation and tissue morphogenesis,” Jiang says.

This study was unusual among palate development studies because Lan’s team used chemical mutagenesis to screen mice pups. They used whole-exome sequencing to identify mutant genes. Finally, they used CRISPR-Cas9 technology to validate the role of Golgb1 in palate development.

CRISPR’s genome-editing capabilities are influencing a wide range of research work at Cincinnati Children’s and around the world.

Jiang says the cleft palate discovery “has wide implication in using the phenotype-based screening to find unexpected biology and disease mechanisms. This was purely discovery-based research that finds a specific cause and validates it.”