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D. J. Wallace, F. Chau, C. Santiago-Turla, P. Challa, P. P. Lee, L. W. Herndon, P. Byers, R. R. Allingham; Osteogenesis Imperfecta and Primary Open Angle Glaucoma: Genetic Analysis of a New Phenotypic Association. Invest. Ophthalmol. Vis. Sci. 2009;50(13):4104.
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Osteogenesis imperfecta (OI) is a group of Mendelian inherited connective tissue disorders characterized by bone fragility and is usually inherited as an autosomal dominant trait. The most common type of OI, type I, typically results from one null allele of collagen type 1 (COL1A1) located on chromosome 17. Ocular findings associated with OI include blue sclerae, low ocular rigidity, and thin corneas. However, there has been no documentation of a link between OI and primary open-angle glaucoma (POAG). We describe three individuals, two isolated cases and one multiplex family, affected by both OI and POAG.
This study was approved by the Duke University IRB. Members of families with OI and POAG were consented and enrolled in the study. Subjects received a complete eye examination including visual acuity, intraocular pressure (IOP), pachymetry, slit lamp exam, dilated fundus exam, and visual fields. Blood samples were obtained for DNA extraction. COL1A1/2 was sequenced and screened for mutations.
All subjects had typical findings of POAG including optic disc cuppping, corresponding visual field loss, and in all cases were associated with elevated IOP. POAG cosegregated with OI in members of the multiplex family. Novel mutations in COL1A1 were found in one sporadic case and one member of the multiplex family. The sporadic case had a unique COL1A1 splice acceptor site mutation in one allele that should lead to a frame shift and mRNA instability. The multiplex family had a single nucleotide insertion in COL1A1 resulting in a frameshift mutation and a premature termination codon. Genetic sequencing of a third subject is in progress.
We have identified two novel mutations in COL1A1 in individuals affected by both OI type I and POAG. This association suggests that mutations in COL1A1 may either be causative for both OI and POAG or that there is a POAG susceptibility gene in linkage disequilibrium with COL1A1.
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