Publications (137) View all
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Article: Maternal Uniparental Isodisomy of Chromosome 6 Reveals a TULP1 Mutation as a Novel Cause of Cone Dysfunction.
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ABSTRACT: PURPOSE: The majority of the genetic causes of autosomal recessive (ar) cone dystrophy (CD) and cone-rod dystrophy (CRD) are currently unknown. We used a high-resolution homozygosity mapping approach in a cohort of patients with CD or CRD to identify new genes for ar cone disorders. DESIGN: Case series. PARTICIPANTS: A cohort of 159 patients with ar CD and 91 patients with CRD. METHODS: The genomes of 83 patients with ar CD and 73 patients with CRD were analyzed for homozygous regions using single nucleotide polymorphism (SNP) microarrays. One patient showed homozygosity of SNPs across chromosome 6, and segregation analysis was performed using microsatellite markers. Direct sequencing of all retinal disease genes on chromosome 6 revealed a novel pathogenic TULP1 mutation in this patient. A cohort of 159 individuals with CD and 91 individuals with CRD was screened for this particular mutation using the restriction enzyme HhaI. The medical history of patients carrying the TULP1 mutation was reviewed and additional ophthalmic examinations were performed, including electroretinography (ERG), perimetry, optical coherence tomography (OCT), fundus autofluorescence (FAF), and fundus photography. MAIN OUTCOME MEASURES: TULP1 mutations, age at diagnosis, visual acuity, fundus appearance, color vision defects, visual field, ERG, FAF, and OCT findings. RESULTS: In 1 patient, homozygosity mapping and subsequent segregation analysis revealed maternal uniparental disomy (UPD) of chromosome 6. A novel homozygous missense mutation (p.Arg420Ser) was identified in TULP1, whereas no mutations were detected in other retinal disease genes on chromosome 6. The mutation affects a highly conserved amino acid residue in the Tubby domain and is predicted to be pathogenic. The same homozygous mutation was also identified in an additional, unrelated patient with CRD. Both patients carrying the p.Arg420Ser mutation presented with a bull's eye maculopathy. The first patient had progressive loss of visual acuity with a relatively preserved ERG, whereas the second patient developed loss of visual acuity, peripheral degeneration, and severely reduced ERG responses in a cone-rod pattern. CONCLUSIONS: Maternal UPD of chromosome 6 unmasked a mutation in the TULP1 gene as a novel cause of cone dysfunction. This expands the disease spectrum of TULP1 mutations from Leber congenital amaurosis and early-onset retinitis pigmentosa to cone-dominated disease. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.Ophthalmology 03/2013; · 5.45 Impact Factor -
Article: Polymorphisms in matrix metalloproteinases MMP1 and MMP9 are associated with primary open-angle and angle closure glaucoma in a Pakistani population.
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ABSTRACT: Matrix metalloproteinases (MMPs) play an important role in remodeling of the extracellular matrix during development and growth of various tissues including the eye. Various functional polymorphisms in MMPs have been implicated in the pathogenesis of different types of glaucoma. The aim of the present study was to investigate the role of various polymorphisms in Pakistani patients with glaucoma. The present case-control study included 112 patients with primary open-angle glaucoma (POAG), 82 patients with primary angle closure glaucoma (PACG), and 118 control subjects. Genotyping of polymorphisms was done using PCR followed by restriction fragment length polymorphism analysis. A significant difference in the genotype frequencies of MMP1 rs1799750 (-1607 1G/2G) was observed between the patients with POAG and the control subjects (p=0.001). This was attributed to the female subjects (p<0.001), while the association was not significant in male subjects (p>0.47). In addition, a significant difference was observed in genotype frequencies of MMP9 rs17576 (c.836A>G) in patients with PACG compared to the control subjects (p<0.001), which after gender stratification remained significant in men (p=0.009) but not in women (p=0.14). No significant associations were found for MMP7 (c.-181T>C) and MMP9 (c.-1562C>T) polymorphisms. Our data suggest that the MMP1 rs1799750 (-1607 1G/2G) and MMP9 rs17576 polymorphisms might be of value for further study as potential gender-dependent risk factors for developing POAG and PACG, respectively, in Pakistan.Molecular vision 01/2013; 19:441-7. · 2.20 Impact Factor -
Article: Analysis of single nucleotide polymorphisms in the SFRS3 and FKBP4 genes in corticosteroid-induced ocular hypertension.
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ABSTRACT: Background: The use of intravitreal triamcinolone acetonide (IVTA) can cause ocular hypertension. This steroid response appears to be heritable and alleles in the SFRS3 and FKBP4 genes have recently been suggested to play a role. The purpose of the present study was to perform an independent replication study to determine whether single nucleotide polymorphisms (SNPs) in SFRS3 and FKBP4 are involved in the steroid response. Materials and Methods: A retrospective case-control study of native Dutch patients was performed who were treated with 4.0mg IVTA. The patients were divided into an intraocular hypertension group (intraocular pressure > 21 mmHg within a year after IVTA) and a non-intraocular hypertension group. The cohort was genotyped for three SNPs: rs7759778 and rs1406945 in SFRS3, and rs2968909 in FKBP4. Results: A total of 102 patients was included: 58 steroid responders and 44 non-responders. No significant differences in demographic parameters or medical history were observed between the study groups. None of the SNPs were found to be significantly associated with the disease as no difference was revealed either in the genotype or allele frequencies between responders and non-responders. Conclusions: This study does not confirm a role for genetic variants in the SFRS3 and FKBP4 genes in the pathogenesis of corticosteroid-induced ocular hypertension. However, our limited sample size may have restricted the power of our study, and we therefore cannot exclude the involvement of these genetic variants in steroid response.Ophthalmic Genetics 08/2012; 33(4):221-4. · 0.93 Impact Factor -
Article: A Nonsense Mutation in PDE6H Causes Autosomal-Recessive Incomplete Achromatopsia.
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ABSTRACT: Achromatopsia (ACHM) is an autosomal-recessive retinal dystrophy characterized by color blindness, photophobia, nystagmus, and severely reduced visual acuity. Its prevalence has been estimated to about 1 in 30,000 individuals. Four genes, GNAT2, PDE6C, CNGA3, and CNGB3, have been implicated in ACHM, and all encode functional components of the phototransduction cascade in cone photoreceptors. Applying a functional-candidate-gene approach that focused on screening additional genes involved in this process in a cohort of 611 index cases with ACHM or other cone photoreceptor disorders, we detected a homozygous single base change (c.35C>G) resulting in a nonsense mutation (p.Ser12(∗)) in PDE6H, encoding the inhibitory γ subunit of the cone photoreceptor cyclic guanosine monophosphate phosphodiesterase. The c.35C>G mutation was present in three individuals from two independent families with a clinical diagnosis of incomplete ACHM and preserved short-wavelength-sensitive cone function. Moreover, we show through immunohistochemical colocalization studies in mouse retina that Pde6h is evenly present in all retinal cone photoreceptors, a fact that had been under debate in the past. These findings add PDE6H to the set of genes involved in autosomal-recessive cone disorders and demonstrate the importance of the inhibitory γ subunit in cone phototransduction.The American Journal of Human Genetics 08/2012; 91(3):527-532. · 10.60 Impact Factor -
Article: Non-syndromic retinal ciliopathies: translating gene discovery into therapy.
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ABSTRACT: Homozygosity mapping and exome sequencing have accelerated the discovery of gene mutations and modifier alleles implicated in inherited retinal degeneration in humans. To date, 158 genes have been found to be mutated in individuals with retinal dystrophies. Approximately one-third of the gene defects underlying retinal degeneration affect the structure and/or function of the 'connecting cilium' in photoreceptors. This structure corresponds to the transition zone of a prototypic cilium, a region with increasing relevance for ciliary homeostasis. The connecting cilium connects the inner and outer segments of the photoreceptor, mediating bi-directional transport of phototransducing proteins required for vision. In fact, the outer segment, connecting cilium and associated basal body, forms a highly specialized sensory cilium, fully dedicated to photoreception and subsequent signal transduction to the brain. At least 21 genes that encode ciliary proteins are implicated in non-syndromic retinal dystrophies such as cone dystrophy, cone-rod dystrophy, Leber congenital amaurosis (LCA), macular degeneration or retinitis pigmentosa (RP). The generation and characterization of vertebrate retinal ciliopathy animal models have revealed insights into the molecular disease mechanism which are indispensable for the development and evaluation of therapeutic strategies. Gene augmentation therapy has proven to be safe and successful in restoring long-term sight in mice, dogs and humans suffering from LCA or RP. Here, we present a comprehensive overview of the genes, mutations and modifier alleles involved in non-syndromic retinal ciliopathies, review the progress in dissecting the associated retinal disease mechanisms and evaluate gene augmentation approaches to antagonize retinal degeneration in these ciliopathies.Human Molecular Genetics 07/2012; 21(R1):R111-24. · 7.64 Impact Factor
