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 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 alpha 5 and beta 3 subunits of the type A gamma-aminobutyric acid receptor (Gabra5 and Gabrb3, respectively), contains a gene(s) (cp1; cleft palate 1) necessary for normal palate development. The cp1 interval extends from the distal breakpoint of the prenatally lethal p83FBFo 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 gamma-aminobutyric acid or its agonists on palate development, suggest the possibility that a particular type A gamma-aminobutyric acid receptor that includes the beta 3 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 mouse suggests that the highly homologous region of the human genome, 15q11-q13, be evaluated for a role(s) in human fetal facial development.
Culiat
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CT
Biology Division, Oak Ridge National Laboratory, TN 37831-8077.
Stubbs
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L
Nicholls
R D
RD
Montgomery
C S
CS
Russell
L B
LB
Johnson
D K
DK
Rinchik
E M
EM
D000818:Animals; D001483:Base Sequence; D015139:Blotting, Southern; D002874:Chromosome Mapping; D002884:Chromosomes, Human, Pair 15; D002972:Cleft Palate / Q000196:embryology / Q000235:genetics* / Q000473:pathology; D003433:Crosses, Genetic; D004247:DNA / Q000235:genetics / Q000302:isolation & purification; D015342:DNA Probes; D005260:Female; D005333:Fetus; D005804:Genes, Lethal; D015894:Genome, Human; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D046911:Macromolecular Substances; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D008969:Molecular Sequence Data; D009838:Oligodeoxyribonucleotides; D016133:Polymerase Chain Reaction; D011963:Receptors, GABA-A / Q000235:genetics*; D017384:Sequence Deletion; D012689:Sequence Homology, Nucleic Acid; D014158:Transcription, Genetic
D015342:DNA Probes; D046911:Macromolecular Substances; D009838:Oligodeoxyribonucleotides; D011963:Receptors, GABA-A; D004247:DNA