causes cleft palate

Researchers have found a gene that causes cleft lip and palate in mice, according to a paper in the April 26 PNAS . The finding also suggests a causal link between smoking and cleft lip and palate in humans, say the authors. Although many cleft palate mouse models exist, cleft lip is rare in mice. The Dancer mutation causes the rarer cleft lip and palate (CL/P), and identification and characterization of this mutation could provide a model to study the molecular pathways involved in both normal craniofacial development and CL/P pathogenesis, lead researcher Rulang Jiang, professor of biology at the University of Rochester, NY, told The Scientist. Dancer is a mutation not studied since the 1950s, which meant that live mice had to be generated from frozen embryos. The team mapped Dancer to a 1-cM region near the centromere of chromosome 19, and in situ hybridization studies showed that one positional candidate gene, T-box transcription factor Tbx10, is ectopically expressed in Dancer mutants. “We picked a few genes including this one, Tbx10. It looked interesting as a candidate for the cleft mutation because there are a few other T-box family genes related in sequence that are involved in human developmental disorders,” said Jiang. However, Tbx1 and Tbx22, which also cause cleft lip and palate in man, are deletion mutations, and because Tbx10 is not expressed in mouse embryos except in the hindbrain, the team initially dismissed the gene. “One day we discussed it—we were fed up—let's look at whether the Dancer mutants have altered expression of Tbx10; the reason behind that was we knew that T-box genes have a dose-dependent response,” said Jiang. The authors found that a 5' region of the p23 gene had been inserted into the first intron of Tbx10, according to Francis H. Ruddle, professor of molecular, cellular, and developmental biology at Yale University. “I think the authors have made a good case for a translocation at the Tbx10 gene altering the expression patterns of that gene, especially with regard to ectopic expression and very possibly overexpression,” said Ruddle, who edited the paper for PNAS but who was not involved in the study. “I think they've established an animal model which could be used to get more insight into the mechanism by which cleft palate is induced.” Martyn Cobourne, senior lecturer at the Department of Orthodontics at Guys Hospital, London, told The Scientist, “The net result is that you get overexpression of Tbx10 all the way through the mouse. It just so happens that in the facial regions for some reason it is having a major effect.” The group modeled the natural mutant with a transgene, said Cobourne, who was not involved in the study. “That's quite clever. They used a different promoter but one they knew would express Tbx10 pretty well ubiquitously, so they've got a good substitute for their natural mutant—and surprise, surprise–the transgenic mouse had a cleft lip and palate.” Cobourne said it was “quite interesting” that the authors observed that the heterozygous Dancer mutants, although exhibiting no native phenotype, were more susceptible to a chemically induced form of clefting. “It reflects, I suspect, what happens in human populations,” he said, explaining that a particular mutation could make an embryo more susceptible to certain environmental effects, such as a mother smoking during pregnancy. “If a child has that particular mutation, the mum smoking five cigarettes per day might just be enough to tip the balance—and that child might have a cleft of the lip and palate,” Cobourne said. Jiang agreed that there might be some significance to this observation. “In fact, the Dancer mutation interacts with the nicotine analog 6-aminonicotinamide,” he said. Correction (posted April 28): Professor Jiang would like us to point out that the statment, "Dancer is a mutation not studied since the 1950s" is incorrect. The Dancer mutation was discovered in the 1950s and was later removed from breeding colonies, "which meant that live mice had to be generated from" a frozen embryo stock. The Dancer mutation was studied in the 1960s - 1980s by several researchers for chromosome linkage mapping and susceptibility to cleft lip formation. The Scientist regrets this error.

causes cleft palate

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