Gene mutation results in missing teeth

December 29, 1999

Approximately 20 percent of the population are born unable to develop a full set of teeth. Although the underlying causes are mostly unknown, members of a Houston, Texas family who lack mainly their first and second molars were found to have a mutation in a gene called PAX9. This is the first report of a human disorder linked to PAX9, one of a family of "master" genes that help determine body shape and organ formation during embryological development. This discovery is an important contribution to understanding the genetics of human tooth development and brings scientists a step closer to someday replicating the process.

Scientists at the University of Texas-Houston Dental Branch and the Baylor College of Medicine discovered the PAX9 mutation in a family in which congenitally absent molars were documented in members of three generations. The finding, published in the January issue of Nature Genetics, was supported by the National Institute of Dental and Craniofacial Research.

The discovery of the PAX9 mutation began with Dr. Rena D'Souza, an associate professor of orthodontics, directing her students to look for patterns of missing teeth in their patients. One of these students, co-author Monica Goldenberg, observed a 13-year-old boy missing 14 permanent teeth. Further investigation revealed that the father and two brothers had a similar condition, and out of 43 family members, 21 were determined to have congenitally missing molars.

"This is an example of an astute clinical observation unveiling a classic pattern of autosomal dominant inheritance, where offspring of both sexes have a 50-50 chance of inheriting a mutated gene and the disorder associated with it," said Dr. D'Souza. "From that point it was a matter of applying the techniques of molecular epidemiology and DNA analysis to identify the gene." By following the inheritance pattern of known DNA markers in affected family members, D'Souza and the Baylor collaborators tracked the responsible gene to a narrow region of chromosome 14, the same region that contained PAX9. A detailed analysis of PAX9 revealed an extra nucleotide in the gene, a mutation which would interrupt gene translation and produce a smaller than normal PAX9 protein.

"PAX9 became an obvious 'candidate' gene for the missing teeth because of what we knew from animal studies," said D'Souza. Mice in which the PAX9 gene has been deliberately obliterated have defects in the limbs, certain glands such as the thymus, and are missing their teeth. These "knockout" mice are deficient in both copies of PAX9 (one copy is inherited from each parent). However, affected members of the Houston family have one normal and one mutated copy and have no detectable anomalies other than missing certain permanent teeth. All of the baby teeth developed normally.

Exactly how the PAX9 mutation affects the development of particular teeth will be the subject of much future research. PAX9 is one of the genes that is activated early in tooth development and works by producing a DNA-binding protein that controls the activity of other genes. D'Souza speculates that the effects of the mutation in the Houston family may mean that there is simply not enough active PAX9 protein to complete the development of all types of teeth. The baby teeth and the anterior permanent teeth may form because they do not require as much PAX9 as the more complex teeth at the back of the mouth. "Just like there is a genetic code for the entire body, each tooth family, such as incisors, cuspids, and molars, may have a unique code that controls development," said D'Souza.
Working with Drs. D'Souza and Goldenberg were Dr. Marion Messersmith from the University of Texas at Houston Health Science Center and the group that performed the gene analysis--Drs. Parimal Das, David Stockton, and Pragna Patel from the Baylor College of Medicine in Houston. The study was supported by the National Institute of Dental and Craniofacial Research, one of the federal National Institutes of Health located in Bethesda, Maryland.

NIH/National Institute of Dental and Craniofacial Research

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