A novel g.-1258G>A mutation in a conserved putative regulatory element of PAX9 is associated with autosomal dominant molar hypodontia

• Published in: Clinical genetics Vol. 80; no. 3; pp. 265 - 272
• Main Authors: Mendoza-Fandino, GA, Gee, JM, Ben-Dor, S, Gonzalez-Quevedo, C, Lee, K, Kobayashi, Y, Hartiala, J, Myers, RM, Leal, SM, Allayee, H, Patel, PI
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.09.2011; Wiley-Blackwell
• Subjects: 3' Untranslated regions; 5' Flanking Region; Animals; Anodontia - genetics; Anodontia - pathology; Base Sequence; Bioinformatics; Biological and medical sciences; Carnivora; Carnivores; Chromosome Disorders; Chromosomes; Chromosomes, Human, Pair 14; Computational Biology - methods; Conserved Sequence; Epithelium; Female; Fundamental and applied biological sciences. Psychology; General aspects. Genetic counseling; Genes, Dominant; Genetic Association Studies; Genetic Linkage; Genetics; Genetics of eukaryotes. Biological and molecular evolution; Genotype; haploinsufficiency; Humans; hypodontia; Linkage analysis; Male; Medical genetics; Medical sciences; Mesenchyme; Molar - pathology; Molars; Molecular and cellular biology; Molecular Sequence Data; multiple-species conserved sequence; Mutation; Odontogenesis - genetics; PAX9; PAX9 Transcription Factor - genetics; Pedigree; Phenotype; Primates; Regulatory sequences; Rodentia; Sequence Alignment; Sequence Analysis, DNA; Teeth; tooth agenesis; Transcription factors; Ungulates; Human; Agenesis; Multiple; hypodontia; Teeth; Molar tooth; Genetic disease; Conserved sequence; Malformation; Autosomal character; molars; PAX9; Genetics; Regulatory sequence; Dominant character; tooth agenesis; Tooth; Mutation; multiple-species conserved sequence
• ISSN: 0009-9163; 1399-0004
• DOI: 10.1111/j.1399-0004.2010.01529.x

Mendoza‐Fandino GA, Gee JM, Ben‐Dor S, Gonzalez‐Quevedo C, Lee K, Kobayashi Y, Hartiala J, Myers RM, Leal SM, Allayee H, Patel PI. A novel g.‐1258G>A mutation in a conserved putative regulatory element of PAX9 is associated with autosomal dominant molar hypodontia. 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.