title: A novel missense mutation in the paired domain of PAX9 causes non-syndromic oligodontia.
abstract: PAX9, a paired domain transcription factor, has important functions in craniofacial and limb development. Heterozygous mutations of PAX9, including deletion, nonsense, or frameshift mutations that lead to a premature stop codon, and missense mutations, were previously shown to be associated with autosomal dominant oligodontia. Here, we report a novel missense mutation that lies in the highly conserved paired domain of PAX9 and that is associated with non-syndromic oligodontia in one family. The mutation, 83G-->C, is predicted to result in the substitution of arginine by proline (R28P) in the N-terminal subdomain of PAX9 paired domain. To rule out the possibility that this substitution is a rare polymorphism and to test whether the predicted amino acid substitution disrupts protein-DNA binding, we analyzed the binding of wild-type and mutant PAX9 paired domain to double-stranded DNA targets. The R28P mutation dramatically reduces DNA binding of the PAX9 paired domain and supports the hypothesis that loss of DNA binding is the pathogenic mechanism by which the mutation causes oligodontia.
authors.affiliation: Department of Cell Biology, Harvard Medical School, 240 Longwood Avenue, Boston, MA 02115, USA. djumlongras@rics.bwh.harvard.edu
authors.forename: Dolrudee
authors.initials: D
authors.lastname: Jumlongras
authors.forename: Jenn-Yih
authors.initials: JY
authors.lastname: Lin
authors.forename: Anas
authors.initials: A
authors.lastname: Chapra
authors.forename: Christine E
authors.initials: CE
authors.lastname: Seidman
authors.forename: Jonathan G
authors.initials: JG
authors.lastname: Seidman
authors.forename: Richard L
authors.initials: RL
authors.lastname: Maas
authors.forename: Bjorn R
authors.initials: BR
authors.lastname: Olsen
mesh_terms: D000293:Adolescent; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000848:Anodontia / Q000175:diagnosis / Q000000981:diagnostic imaging / Q000235:genetics*; D003062:Codon; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics*; D005260:Female; D005982:Glutathione Transferase / Q000378:metabolism; D006579:Heterozygote; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D051764:PAX9 Transcription Factor; D010375:Pedigree; D016133:Polymerase Chain Reaction; D012150:Polymorphism, Restriction Fragment Length; D011392:Proline / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011859:Radiography; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics*
chemical_list: D003062:Codon; D004268:DNA-Binding Proteins; D051764:PAX9 Transcription Factor; C497323:PAX9 protein, human; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors; D011392:Proline; D005982:Glutathione Transferase