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To both characterize the clinical features of large primary open angle glaucoma (POAG) pedigree from a village in southern India and to investigate the genetic basis of their disease.Eighty-four members of a large pedigree received complete eye examinations including slit lamp examination, tonometry, gonioscopy, and ophthalmoscopy. Some were further studied with perimetry. Those diagnosed with POAG were tested for disease-causing mutations in the myocilin and optineurin genes with Sanger sequencing.Fourteen of 84 family members were diagnosed with POAG, while eight were clinically judged to be POAG-suspects. The family structure and the pattern of glaucoma in the pedigree are complex. Features of glaucoma in this pedigree include relatively early age at diagnosis (mean 50 ± 14 years) and maximum intraocular pressures ranging from 14 to 36 mm Hg with a mean of 23 mm Hg ± 6.5 mm Hg. Patients had an average central corneal thickness (mean 529 ± 37.8 microns) and moderate cup-to-disc ratios (0.74 ± 0.14). No mutations were detected in myocilin, optineurin, or TANK binding kinase 1 (TBK1).We report a five-generation pedigree with a complex pattern of POAG inheritance that includes 22 POAG patients and glaucoma suspects. Although the familial clustering of POAG in this pedigree is consistent with dominant inheritance of a glaucoma-causing gene, mutations were not detected in genes previously associated with autosomal dominant glaucoma, suggesting the involvement of a novel disease-causing gene in this pedigree.

PURPOSE Age-related macular degeneration (AMD) is a devastating disease characterized by central vision impairment in individuals with advanced age. Neovascular AMD is a form of end-stage disease in which choroidal vessel outgrowth occurs beneath the retina. While many hypotheses have been raised as to what triggers the formation of pathological choroidal neovascular membranes, the exact mechanism for their initiation remains unresolved. Polymorphisms in the FLT1 gene have previously been associated with neovascular AMD risk, including the rs9943922 single nucleotide polymorphism (SNP). Here, we aimed to determine the association between the high-risk FLT1 genotype and FLT1 protein levels in human retina or retinal pigment epithelium (RPE)/choroid tissue. METHODS Retina and RPE/choroid tissue from 10 human donor eyes was selected from a collection of eyes genotyped for the rs9943922 SNP. Differences in soluble and membrane bound FLT1 protein levels were assessed for retina versus RPE/choroid donor tissue using ELISA and Western blotting analyses. Genotype-associated changes in FLT1 protein levels were also evaluated. RESULTS We found soluble FLT1 levels in the RPE/choroid tissue to be approximately three times higher than that of the retina (p

To determine the role of the SLC4A11 gene in two pedigrees affected with autosomal recessive congenital hereditary endothelial dystrophy (CHED).Nine members of a pedigree from the Kingdom of Saudi Arabia (pedigree 971G) and 2 twins in a pedigree from Bosnia (pedigree GGO413) were diagnosed with autosomal recessive CHED and contributed DNA samples for genetic studies. The proband of each pedigree was tested for disease-causing mutations in the SLC4A11 gene with bi-directional DNA sequencing. Screening assays using restriction enzyme digests were developed to test a cohort of 99 normal control subjects for the presence of SLC4A11 mutations.A novel, homozygous mutation in the SLC4A11 gene (Thr271Met) was detected in the proband of pedigree 971G. Homozygous Thr271Met mutations were detected in all affected members of pedigree 971G. The Thr271Met mutation was not detected in a cohort of 99 normal control subjects. This mutation alters a highly conserved amino acid in the encoded SLC4A11 protein. No SLC4A11 mutations were detected in pedigree GGO413.A novel SLC4A11 mutation (Thr271Met) is associated with autosomal recessive CHED in a pedigree from the Kingdom of Saudi Arabia and provides additional support that mutations in this gene cause disease.

To identify the genetic factors associated with familial non-arteritic anterior ischemic optic neuropathy (NA-AION) in a large pedigree.Eleven family members of a single pedigree, including six affected with NA-AION, underwent detailed clinical examinations. The mitochondrial DNA of the proband was sequenced in its entirety in search of disease-causing mutations associated with NA-AION in the pedigree. A control panel comprising 1488 patients suspected of having Leber hereditary optic neuropathy (LHON) and 97 general-population control subjects was screened for the mitochondrial sequence variant identified in the family.Affected family members were all male and exhibited classic features of NA-AION. Their mean age was 50.2 +/- 5.0 years. A total of 23 sequence variations were detected in the mitochondrial genome of the proband, including one novel sequence variation (G4132A, Ala276Thr) in the NADH dehydrogenase subunit 1 gene (ND1). The G4132A mitochondrial variant was detected in six members of a single pedigree with NA-AION. The G4132A variation was not observed in any of the 1585 subjects in the control panel. Moreover, this variant was not identified in over 2469 ethnically diverse individuals previously evaluated through the Human Mitochondrial Genome Database. None of the three major mutations associated with LHON (G3460A, G11778A, T14484C) were identified in the family.The G4132A mitochondrial variation is associated with familial NA-AION in our pedigree.

Purpose: To determine the role of the single nucleotide polymorphism (SNP) (rs613872) in the TCF4 gene in Fuchs endothelial corneal dystrophy (FECD) in patients from Iowa.Methods: A cohort of 82 patients with FECD and 163 normal control subjects from Iowa were genotyped at the SNP rs613872 using a real-time allelic discrimination assay.Results: The frequencies of the alleles of rs613872 were compared between FECD patients and control subjects. A highly significant association (p-value = 2.96 × 10−10) was detected between this SNP and FECD. Comparison of the genotypes of SNP rs613872 between FECD patients and control subjects produced a p-value of 2.43 × 10−10.Conclusion: Prior reports have shown that SNP rs613872 in the TCF4 gene is highly associated with FECD. Our study confirms this association and shows that the TCF4 gene has an important role in the pathogenesis of corneal disease in patients from Iowa.

Biochemical studies have suggested that elevated serum levels of homocysteine may be associated with primary open-angle glaucoma (POAG)1, 2 and with pseudoexfoliation glaucoma (PEXG).3 More recentl...

Thirty-one members of a family affected with X-linked ocular albinism (OA1) were studied to characterize the clinical phenotype and identify the disease-causing mutation. The family members were examined with ophthalmoscopy, electroretinography, and Goldmann perimetry. Linkage analysis was performed with markers from the OA1 locus. Exons 2 and 8 of the OA1 gene were assayed with the polymerase chain reaction (PCR). The six affected males had visual acuities ranging from 20/40 to 20/200. All had nystagmus, iris transillumination, and foveal hypoplasia. The eldest affected male had 20/40 vision and was asymptomatic. The level of the visual acuity of the affected males was not related to the degree of retinal pigmentation. All seven female carriers had normal visual function but were found to have iris transillumination defects and variable retinal pigmentary appearance ranging from minimal pigmentary disturbance, patchy and diffuse hypopigmentation, to classic 'mud-splattered' appearance. Linkage analysis was consistent with a disease-causing mutation at the OA1 locus. PCR analysis revealed a deletion which includes at least the portion of the OA1 gene between exons 2 and 8. Affected males with X-linked ocular albinism can have a visual disability that ranges from almost none to legal blindness, and the female carriers can have variable retinal pigmentary appearance. Mutation screening of the OA1 gene can be used to confirm the diagnosis in isolated males of some families, and genetic linkage analysis can be used to accurately identify carriers even when the specific mutation cannot be identified.

The gene that causes normal tension glaucoma (NTG) in a large pedigree was recently mapped to a region of chromosome 12q14 (GLC1P) that contains the genes TBK1, XPOT, RASSF3, and GNS. We sought to investigate the structure of the chromosome 12q14 duplication and explore the ocular expression of GLC1P locus genes.The location of the chromosome 12q14 duplication in this pedigree was examined with fluorescent in situ hybridization (FISH) using probes for TBK1 and GNS. The expression pattern of XPOT, TBK1, RASSF3, and GNS was investigated with immunohistochemistry of human eyes.The karyotype of an NTG patient from pedigree GGO-414 was normal and FISH studies demonstrated that the duplicated DNA is organized as a tandem repeat on chromosome 12q14. Of the genes in or near the chromosome 12q14 duplication, TBK1 showed expression in the retina that is specific to the retinal ganglion cells and the retinal nerve fiber layer. Expression of RASSF3 and XPOT was relatively uniform throughout the retina, while GNS expression was expressed in a pattern consistent with Müller cells.Previous studies demonstrated that chromosome 12q14 duplications are associated with NTG inherited as an autosomal dominant trait. FISH studies now demonstrate that the duplicated segments are tandemly organized on chromosome 12q14 in close proximity. The specific expression of TBK1 in human retinal ganglion cells compared to the widespread pattern of expression of neighboring genes provides additional evidence that TBK1 is the glaucoma gene in the chromosome 12q14 duplication within the GLC1P locus.

AbstrA ct Background: Three mitochondrial mutations account for 95% of Leber’s hereditary optic neuropathy (LHON) in the European population: G3640A, G11778A and T14484C. The purpose of the study was to investigate the frequency of these mitochondrial DNA mutations in LHON patients from a South Indian population. Methods: LHON was diagnosed by inheritance pattern, ophthalmologic examination, and by exclusion of non-LHON forms of optic neuropathy. Ninety unrelated LHON patients and 20 at-risk family members (5 with LHON and 15 without LHON) underwent molecular screening for the mitochondrial DNA mutations G3640A, G11778A and T14484C by amplification refractory mutation system (ARMS) polymerase chain reaction (PCR). Positive results were confirmed with bi-directional sequencing. Results: The G11778A mutation was detected in 8 of 90 (8.9%) LHON families. The T14484 mutation was detected in 3 of 90 (3.3%) LHON families. No instances of the G3460A mutation were detected. Other variants were incidentally detected by the DNA sequencing assay. Conclusions: Three mitochondrial mutations (G3640A, G11778A and T14484C) account for the vast majority of LHON cases in Europe. However, these mutations were detected in only 11 (12%) of 90 LHON families from Southern India in our study. These results suggest that a different set of LHON-causing mutations is present in the South Indian population than in the European population. Further study of subjects with LHON from India may lead to the discovery of novel diseasecausing mutations and/or genes.

Objective: To identify the disease-causing mutation in a large 3 generation pedigree of X-linked congenital nystagmus. Methods: Twenty-three members of a single pedigree, including 7 affected males, 2 affected females, 5 obligate carriers, and 9 unaffected family members were tested for mutations in the FRMD7 gene using PCR-based DNA sequencing assays and multiplex PCR assays for deletions. Results: A hemizygous deletion of exons 2, 3, and 4 of FRMD7 was detected in all affected males in the family and was absent from 40 control subjects. Conclusions: A range of missense, nonsense, frameshift, and splicing mutations in FRMD7 have been shown to cause X-linked congenital nystagmus. Here we show for the first time that large intragenic deletions of FRMD7 can also cause this form of nystagmus.

Leber Hereditary Optic Neuropathy (LHON) is a maternally inherited blinding disease caused by missense mutations in the mitochondrial DNA (mtDNA). However, incomplete penetrance and a predominance of male patients presenting with vision loss suggest that modifying factors play an important role in the development of the disease. Evidence from several studies suggests that both nuclear modifier genes and environmental factors may be necessary to trigger the optic neuropathy in individuals harboring an LHON-causing mtDNA mutation. Recently, an optic neuropathy susceptibility locus at Xp21-Xq21 has been reported. In this study, we performed X-chromosomal linkage analysis in a large Brazilian family harboring a homoplasmic G11778A mtDNA mutation on a haplogroup J background. We report the identification of a novel LHON susceptibility locus on chromosome Xq25-27.2, with multipoint non-parametric linkage scores of5.00 (P = 0.005) and a maximum two-point non-parametric linkage score of 10.12, (P = 0.003) for marker DXS984 (Xq27.1). These results suggest genetic heterogeneity for X-linked modifiers of LHON.

(1999). Normal range of hearing associated with myocilin Thr377Met. Ophthalmic Genetics: Vol. 20, No. 3, pp. 205-207.