Identification of a novel frameshift mutation in PITX2 gene in a Chinese family with Axenfeld-Rieger syndrome

Abstract

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.

The diagnosis and phacoemulsification in combination with intraocular lens implantation for an Axenfeld–Rieger syndrome patient with small cornea: a case report

“…Systemic findings include mild midface abnormalities, dental and cardiovascular abnormalities, and redundant umbilical skin [4]. Till now, only very few cases have reported the clinical features of ARS, with retinal detachment, keratoconus, developmental glaucoma and so on [3,[5][6][7][8]. In the present report, small cornea, iris lesions, pupil deformation and cataract were first discovered after the slit microscope examination, and through careful examination of the atrial Angle, the posterior corneal embryonic ring was also found.…”

Mutations in zebrafish pitx2 model congenital malformations in Axenfeld-Rieger syndrome but do not disrupt left-right placement of visceral organs

“…Patients with PITX2 homeodomain mutations at the same amino acid as our pitx2HD alleles developed ARS phenotypes, including malformations of the anterior segment of the eye (Yin et al, 2014). To investigate eye phenotypes observed in pitx2HD mutant zebrafish, we analyzed eye morphology during embryogenesis.…”

The rare Axenfeld–Rieger syndrome with systemic anomalies

“…[ 4 ] Till now, there have been only a very few cases reported the clinical features of ARS in Chinese Han population. [ 5 – 7 ] In the present case, we aimed to report a Chinese female ARS patient with retinal detachment. A brief review of literature on this disease will also be provided.…”