Disruption of the murine Ap2ß1 gene causes nonsyndromic cleft palate.

ABSTRACT

Development of the secondary palate in mammals is a complex process that can be easily perturbed, leading to the common and distressing birth defect cleft palate. Animal models are particularly useful tools for dissecting underlying genetic components of cleft palate. We describe a new cleft palate model resulting from a transgene insertion mutation. Transgene insertional mutagenesis disrupts the genomic organization and expression of the Ap2ß1 gene located on chromosome 11. This gene encodes the ß2-adaptin subunit of the heterotetrameric adaptor protein 2 complex involved in clathrin-dependent endocytosis. Homozygous cleft palate mutant mice express no Ap2ß1 messenger RNA or ß2-adaptin protein and die during the perinatal period. Heterozygous mice are phenotypically normal despite expressing diminished ß2-adaptin messenger RNA and protein compared with wildtype. Remarkably, the paralogous ß1-adaptin subunit of the adaptor protein 1 complex partially substitutes for the missing ß2-adaptin in embryonic fibroblasts from homozygous mutant mice, resulting in assembly of reduced levels of an adaptor protein 2 complex bearing ß1-adaptin. This variant adaptor protein 2 complex is, therefore, apparently capable of maintaining viability of the homozygous mutant embryos until birth but insufficient to support palatogenesis. Nonsyndromic cleft palate in an animal model is associated with disruption of the Ap2ß1 gene.