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Varun Reddy, Sharon Freedman, Shelby Strickland, Yu Chen-Hsin, Rachel W Kuchtey, John Kuchtey, R Rand Allingham, Michael A Hauser; In search of novel CYP1B1 mutations that cause primary congenital glaucoma.. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):2540.
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© ARVO (1962-2015); The Authors (2016-present)
Primary congenital glaucoma (PCG) is an autosomal recessive trait that manifests in the first 3 years of life. PCG is caused by developmental changes in the aqueous humor drainage structures of the eye. These changes result in impaired aqueous humor outflow and increased intraocular pressure (IOP). Mutations in the gene CYP1B1 have been identified in patients with PCG. We screened a dataset of families with PCG for mutations in CYP1B1. The long-term aim of this study is to utilize this dataset for studies in an animal model.
Informed consent was obtained from parents, or in the case of those aged 18 or older, patients. DNA was obtained from blood samples of all subjects. 112 samples from 72 PCG families were obtained. In 10 families, a sample was additionally collected from one parent, and in 16 other families, samples were collected from both parents. CYP1B1 was sequenced using Sanger sequencing. This was a US dataset in which there were 44 male and 28 female children (36 Non-Hispanic white, 31, Non-Hispanic black, 3 Hispanic white, and 2 Non-Hispanic black/white). Genetic variants exhibited by patients were identified via SeattleSeq Annotation, and polymorphism Phenotyping (Polyphen) was used to assess the functional effects of these variants.
Four samples exhibited one PCG causative mutation and three had two or more causative mutations. Four families with CYP1B1 positive probands were identified, all of which represented known PCG causal variants. One proband was homozygous for a 13-bp deletion (GAGTGCAGGCAGA) causing a frameshift mutation in CYP1B1 (SNP rs72549380). Another proband demonstrated a 10 bp duplication (TCATGCCAC) on chromosome 2 as well as a C/T base change producing an Arg390Cys substitution (rs148542782). A third proband was homozygous for a known PCG-associated G/A change causing a Glu387Lys substitution (rs55989760). A fourth, compound-heterozygous proband contained SNPs rs55989760 and rs148542782. (Results summarized in Table 1)
We identified several patients with various combinations of known causative PCG-causative CYP1B1 variants. We must continue to sequence samples of human subjects in an attempt to identify novel PCG causative variants. Functional evaluation of these and other CYP1B1 variants will be performed using an in vivo zebrafish model. We hypothesize that loss of CYP1B1 function will lead to observable changes in anterior eye chamber morphology.
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