title: Identification of a novel frameshift mutation in PITX2 gene in a Chinese family with Axenfeld-Rieger syndrome.
abstract: OBJECTIVE
  Axenfeld-Rieger syndrome (ARS) is phenotypically and genetically heterogeneous. In this study, we identified the underlying genetic defect in a Chinese family with ARS.
  
  
  METHODS
  A detailed family history and clinical data were recorded. The ocular phenotype was documented using slit-lamp photography and systemic anomalies were also documented where available. The genomic DNA was extracted from peripheral blood leukocytes. All coding exons and intron-exon junctions of paired-like homeodomain transcription factor 2 (PITX2) gene and the forkhead box C1 (FOXC1) gene were amplified by polymerase chain reaction (PCR) and screened for mutation by direct DNA sequencing. Variations detected in exon 5 of PITX2 were further evaluated with cloning sequencing. The exon 5 of PITX2 was also sequenced in 100 healthy controls, unrelated to the family, for comparison. Structural models of the wild type and mutant homeodomain of PITX2 were investigated by SWISS-MODEL.
  
  
  RESULTS
  Affected individuals exhibited variable ocular phenotypes, whereas the systemic anomalies were similar. After direct sequencing and cloning sequencing, a heterozygous deletion/insertion mutation c.198_201delinsTTTCT (p.M66Ifs*133) was revealed in exon 5 of PITX2. This mutation co-segregated with all affected individuals in the family and was not found either in unaffected family members or in 100 unrelated controls.
  
  
  CONCLUSIONS
  We detected a novel frameshift mutation p.M66Ifs*133 in PITX2 in a Chinese family with ARS. Although PITX2 mutations and polymorphisms have been reported from various ethnic groups, we report for the first time the identification of a novel deletion/insertion mutation that causes frameshift mutation in the homeodomain of PITX2 protein.
authors.affiliation: Eye Center, the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, China; Zhejiang Provincial Key Lab of Ophthalmology, Hangzhou 310009, China.
authors.forename: Hou-fa
authors.initials: HF
authors.lastname: Yin
authors.forename: Xiao-yun
authors.initials: XY
authors.lastname: Fang
authors.forename: Chong-fei
authors.initials: CF
authors.lastname: Jin
authors.forename: Jin-fu
authors.initials: JF
authors.lastname: Yin
authors.forename: Jin-yu
authors.initials: JY
authors.lastname: Li
authors.forename: Su-juan
authors.initials: SJ
authors.lastname: Zhao
authors.forename: Qi
authors.initials: Q
authors.lastname: Miao
authors.forename: Feng-wei
authors.initials: FW
authors.lastname: Song
mesh_terms: D000869:Anterior Eye Segment / Q000002:abnormalities*; D002681:China; D005124:Eye Abnormalities / Q000235:genetics*; D015785:Eye Diseases, Hereditary; D005260:Female; D016368:Frameshift Mutation / Q000235:genetics*; D005819:Genetic Markers / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics*; D000097577:Homeobox Protein PITX2
chemical_list: D005819:Genetic Markers; D018398:Homeodomain Proteins; D014157:Transcription Factors; D000097577:Homeobox Protein PITX2