Obligatory need for functional Pax9 gene was shown by Pax9 null mouse (Peters et al, 1998). Homozygote knockouts have secondary cleft palate and other abnormalities in craniofacial bones and cartilages, they miss all teeth and derivatives of the third and fourth pharyngeal pouches (thymus, parathyroids and ultimobranchial bodies), they have an extra anterior digit, and they die within few days after birth because of breathing problems. The heterozygotes with one functional allele appear completely normal.
More careful analysis of the developing tooth showed that in Pax9 null allele homozygotes the tooth development is arrested after bud stage while the mesenchyme fails to condense around the growing epithelial bud (Peters et al, 1998). As suggested by the expression pattern, the tissue recombination experiments showed that the defect resides in the knockout mesenchyme, not epithelium. The mesenchyme also fails to express the Bmp4 growth factor and the expression of transcription factors Msx1 and Lef1 is downregulated in mesenchyme after embryonic day 12. The authors suggest that Pax9 regulates the expression of Bmp4 in mesenchymal cells that is needed for the expression of Msx1 and Lef1 after the Bmp4 expression in epithelium is ceased (Peters et al, 1998).
In man, dominant loss-of-funtion mutations of PAX9 cause selective tooth agenesis. The first mutation was a frameshift mutation in the paired box (exon 2) in a family where affected individuals lacked nearly all permanent molars and often also permanent second premolars and lower permanent lateral incisors (Stockton et al, 2000). Subsequently several nonsense and missense mutations in the paired box as well as a frameshift mutation in exon 4 and a deletion of the PAX9 gene have been described (Nieminen et al, 2001; Frazier-Bowers et al, 2002; Das et al, 2002; Das et al, 2003; Mostowska et al, 2003; Lammi et al, 2003). With exception of a few patients, missing of a posterior tooth is dependent on missing of all more posterior teeth in the same quadrant, too. Deciduous teeth are normal in most cases, but reported by (Lammi et al, 2003) and (Das et al, 2002). Also, a reduced size for the teeth that had developed were reported by (2003).
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