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...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.M661fs＊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.M661fs＊133 in PITX2 in a Chinese family with ARS. Although PITX2 mutations and polymorphisms have been re- ported 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.展开更多
基金Project supported by the Qianjiang Talents Project of Zhejiang Province(No.2010R10067)the Zhejiang Key Innovation Team Project of China(No.2009R50039)the Zhejiang Key Laboratory Foundation of China(No.2011E10006)
文摘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.M661fs＊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.M661fs＊133 in PITX2 in a Chinese family with ARS. Although PITX2 mutations and polymorphisms have been re- ported 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.
