title: A novel g.-1258G>A mutation in a conserved putative regulatory element of PAX9 is associated with autosomal dominant molar hypodontia.
abstract: Mutations in the transcription factor PAX9 which plays a critical role in the switching of odontogenic potential from the epithelium to the mesenchyme during tooth development cause autosomal dominant non-syndromic hypodontia primarily affecting molars. Linkage analysis on a family segregating autosomal dominant molar hypodontia with markers flanking and within PAX9 yielded a maximum multipoint LOD score of 3.6. No sequence variants were detected in the coding or 5'- and 3'-untranslated regions (UTRs) of PAX9. However, we identified a novel g.-1258G>A sequence variant in all affected individuals of the family but not in the unaffected family members or in 3088 control chromosomes. This mutation is within a putative 5'-regulatory sequence upstream of PAX9 highly conserved in primates, somewhat conserved in ungulates and carnivores but not conserved in rodents. Bioinformatics analysis of the sequence determined that there was no abolition or creation of a putative binding site for known transcription factors. Based on our previous findings that haploinsufficiency for PAX9 leads to hypodontia, we postulate that the g.-1258G>A variant reduces the expression of PAX9 which underlies the hypodontia phenotype in this family.
authors: Institute for Genetic Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
authors: G A
authors: GA
authors: Mendoza-Fandino
authors: J M
authors: JM
authors: Gee
authors: S
authors: S
authors: Ben-Dor
authors: C
authors: C
authors: Gonzalez-Quevedo
authors: K
authors: K
authors: Lee
authors: Y
authors: Y
authors: Kobayashi
authors: J
authors: J
authors: Hartiala
authors: R M
authors: RM
authors: Myers
authors: S M
authors: SM
authors: Leal
authors: H
authors: H
authors: Allayee
authors: P I
authors: PI
authors: Patel
mesh_terms: D024506:5' Flanking Region; D000818:Animals; D000848:Anodontia / Q000235:genetics* / Q000473:pathology; D001483:Base Sequence; D002335:Carnivora; D025063:Chromosome Disorders; D002883:Chromosomes, Human, Pair 14; D019295:Computational Biology / Q000379:methods; D017124:Conserved Sequence; D005260:Female; D005799:Genes, Dominant; D056726:Genetic Association Studies; D008040:Genetic Linkage; D005838:Genotype; D006801:Humans; D008297:Male; D008963:Molar / Q000473:pathology*; D008969:Molecular Sequence Data; D009154:Mutation; D009805:Odontogenesis / Q000235:genetics*; D051764:PAX9 Transcription Factor / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D012377:Rodentia; D016415:Sequence Alignment; D017422:Sequence Analysis, DNA
chemical_list: D051764:PAX9 Transcription Factor; C497323:PAX9 protein, human