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. 2004 May;74(5):1043-50.
doi: 10.1086/386293. Epub 2004 Mar 23.

Mutations in AXIN2 Cause Familial Tooth Agenesis and Predispose to Colorectal Cancer

Free PMC article

Mutations in AXIN2 Cause Familial Tooth Agenesis and Predispose to Colorectal Cancer

Laura Lammi et al. Am J Hum Genet. .
Free PMC article


Wnt signaling regulates embryonic pattern formation and morphogenesis of most organs. Aberrations of regulation of Wnt signaling may lead to cancer. Here, we have used positional cloning to identify the causative mutation in a Finnish family in which severe permanent tooth agenesis (oligodontia) and colorectal neoplasia segregate with dominant inheritance. Eleven members of the family lacked at least eight permanent teeth, two of whom developed only three permanent teeth. Colorectal cancer or precancerous lesions of variable types were found in eight of the patients with oligodontia. We show that oligodontia and predisposition to cancer are caused by a nonsense mutation, Arg656Stop, in the Wnt-signaling regulator AXIN2. In addition, we identified a de novo frameshift mutation 1994-1995insG in AXIN2 in an unrelated young patient with severe tooth agenesis. Both mutations are expected to activate Wnt signaling. The results provide the first evidence of the importance of Wnt signaling for the development of dentition in humans and suggest that an intricate control of Wnt-signal activity is necessary for normal tooth development, since both inhibition and stimulation of Wnt signaling may lead to tooth agenesis. Our findings introduce a new gene for hereditary colorectal cancer and suggest that tooth agenesis may be an indicator of cancer susceptibility.


Figure  1
Figure 1
Pedigree of the four-generation family and oligodontia phenotypes. A, Pedigree showing autosomal dominant inheritance of oligodontia and colorectal neoplasia. B and C, Panoramic radiographs of the proband (III:8) at age 15 years (B) and her uncle (II:2) at age 34 years (C). Stars indicate congenitally missing permanent teeth. Note that both family members have many persisting deciduous teeth. A persistent deciduous tooth is an often-encountered finding when the corresponding permanent tooth has not developed.
Figure  2
Figure 2
Agenesis of permanent teeth caused by AXIN2 mutations. The number of missing permanent teeth ranged from 8 to 29. Agenesis of deciduous teeth was found in only one individual (IV:1) (not shown).
Figure  3
Figure 3
Multipoint linkage analysis of oligodontia and genetic markers on chromosome 17. LOD scores along chromosome 17 are presented as a function of the genetic distance. The positions of the most important markers used in the analysis are indicated. A genomewide search was performed with Linkage Mapping Set MD10 (ABI), with minor modifications (374 STRP markers), at the Finnish Genome Center. Alleles of markers were amplified using standard PCR methods, AmpliTaq Gold (ABI), and GeneAmp 9700 PCR system (ABI) and were analyzed in a MegaBace 1000 sequencer (Amersham). Allele-calling was made in Genetic Profiler 1.5 (Amersham). Alleles of additional STRP markers were amplified using Dynazyme II DNA Polymerase (Finnzymes) and DNA Engine PTC 200 thermal cycler (MJR) and were analyzed in an ABI 377 fluorescent sequencer. Allele-calling was made with ABI Genotyper software.
Figure  4
Figure 4
Sequence analysis of AXIN2. Genomic DNA was amplified with Dynazyme Ext (Finnzymes) and primers for exons 1–10 of AXIN2 (table A [online only]; GenBank). PCR products were purified with ExoSAP-IT (USB) and were sequenced with ABI BigDye terminator reagents, version 3.1 (Applied Biosystems). The reactions were analyzed in an ABI 3730 DNA sequencer in Molecular Medicine Sequencing Laboratory, Biomedicum Helsinki. A, Chromatogram from sequencing of exon 7 of the proband (III:8) of the three-generation family. All affected family members had the same heterozygous 1966C→T mutation, indicated by the arrow. The mutation was not present in the unaffected family members. B, Chromatogram from sequencing of exon 7 of the sporadic case of oligodontia (de novo mutation). Arrow indicates the position of a heterozygous insertion of a G after nucleotide 1994. C, Partial amino acid sequence from exon 7 of human AXIN2 and consequences of two mutations. Red indicates the mutation in the family affected with oligodontia. Green indicates the de novo frameshift mutation. The Green “Q” indicates the position of the insertion. The asterisk (*) denotes the stop codon. D, Genomic and protein structure of AXIN2. Boxes represent exons; the predicted interaction domains of AXIN2 protein are depicted with colors. APC = adenomatous polyposis coli; GSK = glycogen synthase kinase 3β; Dsh = disheveled homology domain. ATG denotes the beginning of the coding region; TGA denotes the stop codon.
Figure  5
Figure 5
In situ hybridization analysis of Axin2 and Axin1 expression during mouse tooth development. Serial paraffin sections were cut through paraformaldehyde-fixed heads of embryonic and newborn mice. The in situ hybridization with 35S-UTP (Amersham)–labeled riboprobes spanning 1,234 bp of Axin1 and 1,178 bp of Axin2 sequence from exons 1–4 (GenBank) was performed as described elsewhere (Wilkinson and Green 1990). In situ grains in dark-field images of the slides were painted red and superimposed on corresponding bright field images. AE, Frontal sections. F, Sagittal section. AC, E, and F, Axin2. D, Axin1. A, In an E11 embryo, tooth development is initiated. In upper and lower jaws, Axin2 is expressed in the mesenchyme underlying the oral epithelium (arrow). B, At E13, teeth have reached the bud stage. Expression of Axin2 continues in the mesenchyme and is particularly intense adjacent to the tooth buds (arrow). C, In an E14 embryo, teeth are at the cap stage. In addition to the mesenchyme (arrow), expression is seen in the enamel knot (open arrow). D, At E14, Axin1 is expressed weakly and uniformly throughout dental and oral tissues. Similar Axin1 expression was seen at all observed developmental stages (data not shown). E, At E17, tooth development is at the bell stage. Axin2 is expressed in the dental papilla mesenchyme (arrow), as well as in the mesenchymal cells directly underlying all epithelia. F, In a newborn mouse, cell differentiation has started in the molars. Axin2 expression is intense in the layer of mesenchymal odontoblasts and preodontoblasts (open arrow). Intense expression is also seen under the oral epithelium (arrow). oe = oral epithelium; de = dental epithelium; m = mesenchyme; t = tongue; M1 = first molar; M2 = second molar; E = embryonic day.

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