Compromised actin dynamics underlie the orofacial cleft in Baraitser-Winter Cerebrofrontofacial Syndrome with a variant in ACTB

Craniofacial anomalies encompassing the orofacial cleft are associated with >30% of systemic congenital malformations. Baraitser-Winter Cerebrofrontofacial syndrome (BWCFF) is a rare genetic disorder attributed to variants in the actin beta ( ACTB ) or actin gamma genes that are correlated with a range of craniofacial abnormalities, including cleft lip and/or palate. The underlying pathological mechanism of BWCFF remains elusive, and it is necessary to investigate the etiology of orofacial clefts in BWCFF.

In this study, we identified a missense variant (c.1043C>T: p.S348L) in the ACTB gene from a patient with BWCFF and concomitant cleft lip and palate. Furthermore, we performed functional assessments of this variant using various disease models such as the MDCK cell line and Xenopus laevis . These models revealed a compromised capacity of mutated ACTB to localize at the epithelial junction, consequently affecting the behavior of epithelial cells. Additionally, we made the noteworthy discovery that mutated ACTB exhibited an impaired ability to bind PROFILIN1, a critical factor in actin polymerization. This defective ability may contribute to the molecular etiology of aberrant epithelial cell adhesion and migration, resulting in orofacial cleft formation in BWCFF.

Author Summary

Advances in clinical sequencing have rapidly elucidated the genetic basis of rare diseases affecting multiple organs. In this study, we investigate the role of a variant in the ACTB gene, which is fundamental to cell structure, in causing orofacial clefts in the Baraitser-Winter Cerebrofrontofacial Syndrome (BWCFF), known for its distinctive facial anomalies. Using epithelial cell lines and frog embryo models, we investigated the effects of the ACTB gene alteration on cellular functions. Our results indicate that this genetic change disrupts the normal adhesion and movement of epithelial cells, processes that are critical for facial development. This research underscores the importance of the ACTB gene in shaping the face and suggests new directions for future research, potentially informing the diagnosis and treatment of BWCFF and related conditions.