Msx1 function is mandatory for tooth development

Targeted inactivation of Msx1 in transgenic mice leads to an arrest of tooth development at the bud stage. These mice exhibit also other developmental defects, e.g. cleft palate. Heterozygotes are normal (Satokata et al, 1994). If also the Msx2 gene is rendered inactive ("double knockout"), the tooth development is arrested even earlier, at the initiation stage (Bei et al, 1998).

There is also evidence of involvement of human MSX1 in tooth development. A single point mutation in the homeodomain of MSX1 was found to segregate with oligodontia (lack) of all permanent second premolars and third molars (Vastardis et al, 1996). Most affected members also lacked some other teeth (first permanent and molars, the lack of which is very uncommon, or first incisors). However, the affected members of the family were all reported to have complete deciduous dentition, a state that would be in accordance with the lack of defects in heterozygous mice. Functional analysis later showed that the point mutation causes structural perturbation and reduced thermostability of the MSX1 protein, thus suggesting that the phenotype is caused by smaller amount of the functional protein (haploinsufficiency, Hu et al, 1998). The selective effect on only certain human teeth of the single amino acid change in a protein that appears to be present in all teeth can best be interpreted in terms of an existing threshold in some point of the development that must be overcome to produce a complete tooth.

Several other mutations in MSX has since been described in three other families. These include nonsense mutations in exon 1 (van den Boogaard et al, 2000) and exon2 (Jumlongras et al, 2001) as well as a missense mutation in exon2 (Lidral et al, 2002). The pattern of missing teeth in these families resembled that in the family of Vastardis et al, 1996, as the teeth most severely affected were second premolars and third molars. However, there was considerable variability for missing of other teeth. Also, the exon1 mutation was also associated with oral clefts in some of the family members (van den Boogaard et al, 2000) and the exon2 nonsense mutation with nail dysplasia (Jumlongras et al, 2001).

The latter studies support the conclusion that the oligodontia is caused by MSX1 haploinsufficiency. The variability may be explained by slightly different overall effect by different mutations as it is known that Msx1 interacts with various other proteins or it may be explained by different genetic background in the families. The haploinsufficiency as a major mechanism is further supported by the study of (Nieminen et al, 2003) which showed that deletions of MSX1 caused a similar pattern of oligodontia.

The previous studies show that mutations in MSX1 cause oligodontia, a severe type of congenital tooth aganesis. However, it is obvious that these represent only a minority of all congenital tooth agenesis or even the severe phenotypes. Several studies have failed to find mutations in MSX1 in studies in Finnish families have not shown any involvement of MSX1 to hypodontia, the common type of tooth agenesis (Nieminen et al, 1995). On the contrary, most of the families show recombinations between MSX1 and hypodontia. The type of hypodontia in these families is not as uniform as described above. Instead, the affected may lack only one or a few teeth (incisors or second premolars) or they may have malformation of second upper incisors, so called peg-shaped incisors. This condition runs as a dominant trait in families, and it appears that some carriers of the gene have no defects at all (reduced penetrance).

MSX1 has also been implicated with oral clefting. The homozygous null mutant mice exhibit cleft palate (Satokata et al, 1994). A polymorphism in MSX1 was associated with clefting (Lidral et al, 1998), and recently several alterations in MSX1 were found in a wide study of oral cleft patients (Jezewski et al, 2003). Different types of clefts were also found in some patients in one of the families with a MSX1 exon 1 nonsense mutation (van den Boogaard et al, 2000). However, oral clefts were not seen in patients with heterozygous MSX1deletions (Nieminen et al, 2003).

Jackson Mouse Genome Database Transgene Database OMIM

Text last edited 31.12.2000 by P.N. , page last created 10.12.2004 by P.N.