Three genes (Gabrg3, GabraS, and Gabrb3) encoding the y3, as, and A subunits of the type A y-aminobutyric acid receptor, respectively, are known to map near the pink-eyed dilution (p) In adult vertebrate brain, binding of the neurotransmitter 'y-aminobutyric acid to type A (GABAA) receptors results in the opening ofthe receptor's integral membrane Cl-channel, which leads to an inhibition of neuronal activity (1,2). Other studies have suggested that during early postnatal development this receptor-ligand interaction has an excitatory function (3). The clinical importance of understanding the biochemistry and the regulation of expression of GABAA receptors is realized when one considers that these receptors are also targets for a wide variety of pharmaceutically important drugs, such as antiepileptic agents, anxiolytics, muscle relaxants, sedatives, and hypnotics (2, 4).Comparison of amino acid sequences predicted from cloned cDNAs reveals that GABAA receptors belong to a superfamily ofligand-gated ion channels, which also includes the glycine and nicotinic acetylcholine receptors (1,2,5). Current data strongly suggest an extraordinary diversity of GABAA receptors (referred to as subtypes) formed by combinations of four to five subunit polypeptides, although the exact subunit composition is not yet known for any native receptor. For example, at least five GABAA-receptor subtypes have been detected in neurons by in situ immunofluorescence staining with subunit-specific antibodies (6). The 16 subunits so far identified are grouped into five classes: ala, p.1i4, y1-3, 8, and pi-2 (4, 36). Members of the same class exhibit 70-80% amino acid-sequence homology as compared with 30-40%o between different classes.

Genetic and molecular analyses of a number of radiation-induced deletion mutations of the pink-eyed dilution (p) locus in mouse chromosome 7 have identified a specific interval on the genetic map associated with a neonatally lethal mutation that results in cleft palate. This interval, closely linked and distal to p, and bracketed by the genes encoding the Ot5 and 13 subunits of the type A y-aminobutyric acid receptor (GabraS and Gabrb3, respectively), contains a gene(s) (cpl; cleft palate 1) necessary for normal palate development. The cpl interval extends from the distal breakpoint of the prenatally lethal p8FBFo deletion to the Gabrb3 locus. Among 20 p deletions tested, there was complete concordance between alterations at the Gabrb3 transcription unit and inability to complement the cleft-palate defect. These mapping data, along with previously described in vivo and in vitro teratological effects of v-aminobutyric acid or its agonists on palate development, suggest the possibility that a particular type A y-aminobutyric acid receptor that includes the P3 subunit may be necessary for normal palate development. The placement ofthe cpl gene within a defined segment of the larger D1SS12h (p)-D15S9h-1 interval in the mouse suggests that the highly homologous region of the human genome, 15qI1-q13, be evaluated for a role(s) in human fetal facial development.

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