CONCORDANCE BETWEEN ISOLATED CLEFT-PALATE IN MICE AND ALTERATIONS WITHIN A REGION INCLUDING THE GENE ENCODING THE BETA(3)-SUBUNIT OF THE TYPE-A GAMMA-AMINOBUTYRIC-ACID RECEPTOR

Genetic and molecular analyses of a number of radiation-induced deleti on mutations of the pink-eyed dilution (p) locus in mouse chromosome 7 have identified a specific interval on the genetic map associated wit h a neonatally lethal mutation that results in cleft palate. This inte rval, closely linked and distal to p, and bracketed by the genes encod ing the alpha5 and beta3 subunits of the type A gamma-aminobutyric aci d receptor (Gabra5 and Gabrb3, respectively), contains a gene(s) (cp1; cleft palate 1) necessary for normal palate development. The cp1 inte rval extends from the distal breakpoint of the prenatally lethal p83FB Fo deletion to the Gabrb3 locus. Among 20 p deletions tested, there wa s complete concordance between alterations at the Gabrb3 transcription unit and inability to complement the cleft-palate defect. These mappi ng data, along with previously described in vivo and in vitro teratolo gical effects of gamma-aminobutyric acid or its agonists on palate dev elopment, suggest the possibility that a particular type A gamma-amino butyric acid receptor that includes the beta3 subunit may be necessary for normal palate development. The placement of the cp1 gene within a defined segment of the larger D15S12h (p)-D15S9h-1 interval in the mo use suggests that the highly homologous region of the human genome, 15 q11-q13, be evaluated for a role(s) in human fetal facial development.