title: A novel MSX1 intronic mutation associated with autosomal dominant non-syndromic oligodontia in a large Chinese family pedigree.
abstract: BACKGROUND
  Tooth agenesis is a common developmental dental anomaly. The aim of the study was to identify the causal genetic mutation in a four-generation Chinese family affected with non-syndromic autosomal dominant tooth agenesis.
  
  
  METHODS
  Genome-wide scanning was performed using the Illumina Linkage-12 array. Genotyping of short tandem repeat markers was used to finely map the causative locus. Haplotype analysis and Sanger sequencing was performed to precisely locate the position and nature of the gene defect.
  
  
  RESULTS
  Clinical examination of the available 23 family members showed variable tooth agenesis in 10 subjects, ranging from oligodontia to mild hypodontia. Genome-wide scanning and haplotype analyses identified the 4p16.1-p16.3 region with a maximum multi-point LOD score of 3.50, which overlapped with the MSX1 gene. A single heterozygous point mutation IVS1-5 G>A in the MSX1 gene was exclusively detected in the 10 family members affected with tooth agenesis. Sequencing of MSX1 cDNA revealed that the intronic mutation did not affect the normal splicing pattern of the pre-mRNA. However, real-time qPCR analysis of lymphocyte RNA showed that the level of MSX1 mRNA was significantly decreased in individuals heterozygous for the mutation.
  
  
  CONCLUSIONS
  We identified and characterized a novel intronic mutation in the MSX1 gene in a large Chinese pedigree, adding to the small repertoire of MSX1 mutations associated with autosomal dominant tooth agenesis. We hypothesize that the variable degree of tooth agenesis observed in each affected individual may be due to sub-optimal levels of MSX1 expression during critical stages tooth development.
authors.affiliation: State Key Laboratory of Medical Genetics, Central South University, Changsha, Hunan 410078, China; Children's Hospital of Shanxi, Women Health Center of Shanxi, Taiyuan, Shanxi 030013, China.
authors.forename: Jinjie
authors.initials: J
authors.lastname: Xue
authors.affiliation: Department of Stomatology, Xiangya Hospital, Central South University, Changsha, Hunan 410078, China.
authors.forename: Qingping
authors.initials: Q
authors.lastname: Gao
authors.affiliation: State Key Laboratory of Medical Genetics, Central South University, Changsha, Hunan 410078, China.
authors.forename: Yanru
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Department of Stomatology, Xiangya Hospital, Central South University, Changsha, Hunan 410078, China.
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Medical Genetics, Central South University, Changsha, Hunan 410078, China.
authors.forename: Pu
authors.initials: P
authors.lastname: Yang
authors.affiliation: Children's Hospital of Shanxi, Women Health Center of Shanxi, Taiyuan, Shanxi 030013, China; Department of Anatomy and Developmental Biology, Monash University, Clayton, Victoria 3800, Australia.
authors.forename: David S
authors.initials: DS
authors.lastname: Cram
authors.affiliation: State Key Laboratory of Medical Genetics, Central South University, Changsha, Hunan 410078, China.
authors.forename: Desheng
authors.initials: D
authors.lastname: Liang
authors.affiliation: State Key Laboratory of Medical Genetics, Central South University, Changsha, Hunan 410078, China. Electronic address: wulingqian@sklmg.edu.cn.
authors.forename: Lingqian
authors.initials: L
authors.lastname: Wu
mesh_terms: D000293:Adolescent; D000848:Anodontia / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D002681:China; D005260:Female; D006801:Humans; D007438:Introns / Q000235:genetics*; D051957:MSX1 Transcription Factor / Q000235:genetics*; D008297:Male; D009154:Mutation; D010375:Pedigree
chemical_list: D051957:MSX1 Transcription Factor; C484083:MSX1 protein, human
keywords: Genome-wide scan; Intronic mutation; MSX1 homeobox gene; Permanent teeth; Short tandem repeat; Tooth agenesis