title: Novel PAX9 mutations cause non-syndromic tooth agenesis.
abstract: PAX9 is a transcription factor expressed in the tooth mesenchyme during tooth morphogenesis. In Pax9-null mice, tooth development is arrested at the bud stage. In humans, heterozygous mutations in PAX9 have been associated with non-syndromic tooth agenesis, predominantly in the molars. Here, we report 2 novel mutations in the paired domain of PAX9, a three-nucleotide deletion (73-75 delATC) and a missense mutation (C146T), in two unrelated Japanese patients with non-syndromic tooth agenesis. The individual with the 73-75del ATC mutation was missing all maxillary molars and mandibular second and third molars. The individual with the C146T mutation was missing the mandibular central incisors, maxillary second premolars, and first molars, along with all second and third molars. Both mutations affected amino acids that are highly conserved among different species and are critical for DNA binding. When both mutants were transfected to COS7 cells, nuclear localization of PAX9 proteins was not affected. However, reduced expression of the mutant proteins and almost no transcriptional activity of the target BMP4 gene were observed, suggesting haploinsufficiency of PAX9 as the cause of non-syndromic tooth agenesis.
authors.affiliation: Department of Orthodontics and Dentofacial Orthopedics, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan.
authors.forename: S N
authors.initials: SN
authors.lastname: Mitsui
authors.forename: A
authors.initials: A
authors.lastname: Yasue
authors.forename: K
authors.initials: K
authors.lastname: Masuda
authors.forename: K
authors.initials: K
authors.lastname: Watanabe
authors.forename: S
authors.initials: S
authors.lastname: Horiuchi
authors.forename: I
authors.initials: I
authors.lastname: Imoto
authors.forename: E
authors.initials: E
authors.lastname: Tanaka
mesh_terms: D000225:Adenine; D000818:Animals; D000848:Anodontia / Q000235:genetics*; D001641:Bicuspid / Q000002:abnormalities; D055415:Bone Morphogenetic Protein 4 / Q000235:genetics; D019556:COS Cells; D002522:Chlorocebus aethiops; D017124:Conserved Sequence / Q000235:genetics; D003596:Cytosine; D005091:Exons / Q000235:genetics; D005822:Genetic Vectors / Q000235:genetics; D057895:Haploinsufficiency / Q000235:genetics; D006579:Heterozygote; D006801:Humans; D007180:Incisor / Q000002:abnormalities; D008963:Molar / Q000002:abnormalities; D008964:Molar, Third / Q000002:abnormalities; D009154:Mutation / Q000235:genetics*; D020125:Mutation, Missense / Q000235:genetics; D009805:Odontogenesis / Q000235:genetics; D051764:PAX9 Transcription Factor / Q000235:genetics*; D010375:Pedigree; D010957:Plasmids / Q000235:genetics; D017384:Sequence Deletion / Q000235:genetics; D013941:Thymine; D014083:Tooth Germ / Q000196:embryology; D014162:Transfection
chemical_list: C525809:BMP4 protein, human; D055415:Bone Morphogenetic Protein 4; D051764:PAX9 Transcription Factor; C497323:PAX9 protein, human; D003596:Cytosine; D000225:Adenine; D013941:Thymine
keywords: Bmp4 promoter assay; haploinsufficiency; novel mutations; oligodontia; paired domain; transcription factor