Abstract
PurposeAxenfeld-Rieger syndrome (ARS) is an autosomal dominant disorder characterized by ocular anterior segment abnormalities. In the current study, we describe clinical and genetic findings in a Chinese ARS pedigree.MethodsAn ARS pedigree was recruited and patients were given comprehensive ophthalmic examinations and general physical examinations. DNA from the proband II:2 was used for exome sequencing. Sanger sequencing was utilized to identify and validate PITX2 variations. qPCR and western blotting were performed to detect PITX2 expression in immortalized peripheral blood lymphocytes.ResultsAll affected family members showed typical ocular abnormalities, including iris atrophy, corectopia, shallow anterior chamber, complete or partial angle closure, and advanced glaucoma. They also exhibited systemic anomalies, such as microdontia, hypodontia, and redundant periumbilical skin. A heterozygous splice-site variation c.390 + 1G > A in PITX2, which might lead to a truncated PITX2 protein (p.Val131IlefsX127), was found in the proband. Sanger sequencing validated that the variation completely co-segregated with the ARS phenotype within this family and was absent in 100 unrelated controls. Western blotting revealed that the nuclear PITX2 protein was significantly decreased in patients compared with controls. Nonetheless, there was no significant difference in the total PITX2 protein level, consistent with qPCR results showing no alteration in PITX2 mRNA levels in the patient group.ConclusionsPITX2 c.390 + 1G > A (p.Val131IlefsX127) was a novel genetic etiology of the ARS pedigree. The mutation leads to decreased nuclear PITX2, indicating lower transcriptional activity.
Highlights
Axenfeld-Rieger syndrome (ARS) is an autosomal dominant hereditary disease with highly genetic heterogeneity [1]
The major candidate genes are paired-like homeodomain 2 (PITX2), located at 4q25, which plays a fundamental role in genetic control of ocular anterior segment development [2], and forkhead box C1 (FOXC1), located at 6p25, which acts as an important regulator of cell migration and differentiation during embryogenesis [3]
ARS, which is caused by mutations of either PITX2 or FOXC1, exhibits considerable phenotypic heterogeneity
Summary
Axenfeld-Rieger syndrome (ARS) is an autosomal dominant hereditary disease with highly genetic heterogeneity [1]. The major candidate genes are paired-like homeodomain 2 (PITX2), located at 4q25, which plays a fundamental role in genetic control of ocular anterior segment development [2], and forkhead box C1 (FOXC1), located at 6p25, which acts as an important regulator of cell migration and differentiation during embryogenesis [3]. Mutations in these two genes are found in 40%–70% of ARS patients [4, 5]. Onset of secondary glaucoma typically occurs before the teenage years [9]
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