FAF1, a Gene that Is Disrupted in Cleft Palate and Has Conserved Function in Zebrafish

Abstract

Cranial neural crest (CNC) is a multipotent migratory cell population that gives rise to most of the craniofacial bones. An intricate network mediates CNC formation, epithelial-mesenchymal transition, migration along distinct paths, and differentiation. Errors in these processes lead to craniofacial abnormalities, including cleft lip and palate. Clefts are the most common congenital craniofacial defects. Patients have complications with feeding, speech, hearing, and dental and psychological development. Affected by both genetic predisposition and environmental factors, the complex etiology of clefts remains largely unknown. Here we show that Fas-associated factor-1 (FAF1) is disrupted and that its expression is decreased in a Pierre Robin family with an inherited translocation. Furthermore, the locus is strongly associated with cleft palate and shows an increased relative risk. Expression studies show that faf1 is highly expressed in zebrafish cartilages during embryogenesis. Knockdown of zebrafish faf1 leads to pharyngeal cartilage defects and jaw abnormality as a result of a failure of CNC to differentiate into and express cartilage-specific markers, such as sox9a and col2a1. Administration of faf1 mRNA rescues this phenotype. Our findings therefore identify FAF1 as a regulator of CNC differentiation and show that it predisposes humans to cleft palate and is necessary for lower jaw development in zebrafish.

A Genome-wide Association Study of Nonsyndromic Cleft Palate Identifies an Etiologic Missense Variant in GRHL3

“…26,47,48 Small sample sizes might have also contributed to our failure to replicate a previously reported association with FAF1. 8 In multiple cohorts of European ancestry, the TT genotype of rs1149795 (near FAF1) was associated with a 1.47-fold increased risk of CP. However, our present study was insufficiently powered to detect associations with modest effect.…”

“…One gene that might influence risk for CP is FAF1 (MIM: 604460), which was initially identified from a translocation in a multiplex CP-affected family with Pierre Robin sequence (MIM: 261800). 8 Subsequently, SNPs near FAF1 were shown to be associated with nonsyndromic CP in trios of European ancestry. 8 However, the FAF1 locus only partially accounts for the heritability of CP, and therefore, we hypothesize that other risk loci exist.…”

“…8 Subsequently, SNPs near FAF1 were shown to be associated with nonsyndromic CP in trios of European ancestry. 8 However, the FAF1 locus only partially accounts for the heritability of CP, and therefore, we hypothesize that other risk loci exist. Whereas five GWASs of CL/P have identified at least 15 genetic loci with compelling statistical support, 9 only one GWAS for CP has been completed with no statistically significant SNP main effects for FAF1 or any other gene.…”

PDGFRa mutations in humans with isolated cleft palate

“…The role of FAF1 in lower jaw development including palate was also strengthened by the presence of severe jaw defects in faf1-knockdown zebrafish. 5 A similar approach also identified another candidate gene for CP. Disruption of platelet-derived growth factor receptor alpha (Pdgfra) in zebrafish by Mirn140 was found to cause craniofacial abnormalities including cleft palate.…”

Palatogenesis: morphogenetic and molecular mechanisms of secondary palate development

“…In addition, the chick is a classical experimental embryology model system in which palate morphogenesis has been characterized (Ferguson, 1988). More recently, several studies have used the morpholino knockdown approach in zebrafish to assess gene function in palate development (Ghassibe-Sabbagh et al, 2011;Nakamura et al, 2011;Swartz et al, 2011). It is therefore important to understand the extent to which mechanisms for palatogenesis are conserved across these species.…”