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

• Published in: Human molecular genetics Vol. 33; no. 22; pp. 1975 - 1985
• Main Authors: Tsujimoto, Takayuki, Ou, Yushi, Suzuki, Makoto, Murata, Yuka, Inubushi, Toshihiro, Nagata, Miho, Ishihara, Yasuki, Yonei, Ayumi, Miyashita, Yohei, Asano, Yoshihiro, Sakai, Norio, Sakata, Yasushi, Ogino, Hajime, Yamashiro, Takashi, Kurosaka, Hiroshi
• Format: Journal Article
• Language: English
• Published: England 08.11.2024
• Subjects: orofacial cleft; rare disease; model animal; ACTB; Baraitser-Winter Cerebrofrontofacial syndrome
• ISSN: 0964-6906; 1460-2083; 1460-2083
• DOI: 10.1093/hmg/ddae133

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 patients with BWCFF. In this study, we identified a missense variant (c.1043C > T: p.S348L) in the ACTB gene of 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 to the epithelial junction, consequently affecting the behavior of epithelial cells. Additionally, we discovered that the 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.