Prevalence of Disease-Causing Mutations in Families with Autosomal Dominant Retinitis Pigmentosa: A Screen of Known Genes in 200 Families

Sullivan, Lori S.; Bowne, Sara J.; Birch, David G.; Hughbanks-Wheaton, Dianna K.; Heckenlively, John R.; Lewis, Richard A.; Garcia, Charles A.; Ruiz, Richard; Blanton, Susan H.; Northrup, Hope; Gire, Anisa; Seaman, Robyn; Duzkale, Hatice; Spellicy, Catherine J.; Zhu, Jiankun; Shankar, Suma P.; Daiger, Stephen P.

doi:10.1167/iovs.05-1443

Cited by 233 publications

(207 citation statements)

References 63 publications

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“…[22][23][24][25] The SIFT programme was applied to prioritize three missense mutations in the exon 2 coding region of COL8A2. The tolerance index score for each mutation was 0.00, predicting a deleterious effect for each.…”

Section: Discussionmentioning

confidence: 99%

Q455V mutation in COL8A2 is associated with Fuchs' corneal dystrophy in Korean patients

Mok

Kim

Joo

2008

Eye

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Purpose To investigate the possibility of collagen type VIII a2 (COL8A2) as a potential susceptibility gene for Korean patients with Fuchs' corneal dystrophy (FECD), we performed mutation screening of the COL8A2 gene. Methods A total of 25 FECD patients were screened, including 15 patients from six pedigrees with early onset FECD and an additional 10 unrelated patients, all of Korean ancestry. Seventy-three control individuals without corneal disease were selected from the general population. PCRFSSCP and direct sequencing were used to screen genetic variations in COL8A2. The pathogenic impact of these sequence variants was evaluated through the SIFT and PolyPhen algorithms.Results We have identified a novel heterozygous mutation, Q455V, in exon 2 of COL8A2. All patients of Korean pedigrees with FECD had the Q455V mutation, and two out of nine unrelated cases also had this mutation. But it was not present in unaffected individuals from these pedigrees or from control groups. Two heterozygous missense mutations, R155Q and T502M, were also observed, but, they showed no significant difference between FECD patients and controls. The allele frequencies of A35A and G495G, which were synonymous substitutions, were significantly associated with FECD. Both Q455V and T502M were predicted as deleterious mutations by computational methods using PolyPhen and SIFT. Conclusions Our data constitute the first report of a heterozygous Q455V mutation of the COL8A2 gene in Korean patients with FECD. Q455V may be the causative defect in the development and progression of Korean FECD patients.

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Section: Discussionmentioning

confidence: 99%

Q455V mutation in COL8A2 is associated with Fuchs' corneal dystrophy in Korean patients

Mok

Kim

Joo

2008

Eye

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“…This disease is estimated to affect nearly 1 million people worldwide and leads to a substantial decrease in the ability of affected individuals to lead independent lives and conduct activities of daily living (1,2). A heterogeneous genetic condition, RP is linked to more than 60 genes, most of which occur in genes that are exclusively expressed in rod photoreceptors (5)(6)(7). Due to the genetic diversity of RP, any therapy that is gene specific can only benefit a small fraction of patients with RP.…”

Section: Introductionmentioning

confidence: 99%

Reprogramming towards anabolism impedes degeneration in a preclinical model of retinitis pigmentosa

Zhang

Justus

et al. 2016

Hum. Mol. Genet.

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Retinitis pigmentosa (RP) is an incurable neurodegenerative condition featuring photoreceptor death that leads to blindness. Currently, there is no approved therapeutic for photoreceptor degenerative conditions like RP and atrophic age-related macular degeneration (AMD). Although there are promising results in human gene therapy, RP is a genetically diverse disorder, such that gene-specific therapies would be practical in a small fraction of patients with RP. Here, we explore a non-genespecific strategy that entails reprogramming photoreceptors towards anabolism by upregulating the mechanistic target of rapamycin (mTOR) pathway. We conditionally ablated the tuberous sclerosis complex 1 (Tsc1) gene, an mTOR inhibitor, in the rods of the Pde6b H620Q/H620Q preclinical RP mouse model and observed, functionally and morphologically, an improvement in the survival of rods and cones at early and late disease stages. These results elucidate the ability of reprogramming the metabolome to slow photoreceptor degeneration. This strategy may also be applicable to a wider range of neurodegenerative diseases, as enhancement of nutrient uptake is not gene-specific and is implicated in multiple pathologies. Enhancing

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“…1 Affected people have been reported in diverse ethnic groups worldwide. [2][3][4][5][6] Recently, mutations in two genes, MAK 7,8 and DHDDS, 9,10 were found to cause autosomal recessive RP (arRP) in patients of Ashkenazi Jewish ancestry, i.e., in descendants of Israelites who migrated from the Middle East to Central and Eastern Europe during the Middle Ages.…”

Section: Introductionmentioning

confidence: 99%

Two specific mutations are prevalent causes of recessive retinitis pigmentosa in North American patients of Jewish ancestry

Venturini

Koskiniemi-Kuendig

Harper

et al. 2015

Genetics in Medicine

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Purpose: Retinitis pigmentosa is a Mendelian disease with a very elevated genetic heterogeneity. Most mutations are responsible for less than 1% of cases, making molecular diagnosis a multigene screening procedure. In this study, we assessed whether direct testing of specific alleles could be a valuable screening approach in cases characterized by prevalent founder mutations. Methods:We screened 275 North American patients with recessive/isolate retinitis pigmentosa for two mutations: an Alu insertion in the MAK gene and the p.Lys42Glu missense in the DHDDS gene. All patients were unrelated; 35 reported Jewish ancestry and the remainder reported mixed ethnicity. Results:We identified the MAK and DHDDS mutations homozygously in only 2.1% and 0.8%, respectively, of patients of mixed ethnicity, but in 25.7% and 8.6%, respectively, of cases reporting Jewish ancestry. Haplotype analyses revealed that inheritance of the MAK mutation was attributable to a founder effect. Conclusion: In contrast to most mutations associated with retinitis pigmentosa-which are, in general, extremely rare-the two alleles investigated here cause disease in approximately one-third of North American patients reporting Jewish ancestry. Therefore, their screening constitutes an alternative procedure to large-scale tests for patients belonging to this ethnic group, especially in timesensitive situations. Genet Med advance online publication 25 September 2014

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Prevalence of Disease-Causing Mutations in Families with Autosomal Dominant Retinitis Pigmentosa: A Screen of Known Genes in 200 Families

Cited by 233 publications

References 63 publications

Q455V mutation in COL8A2 is associated with Fuchs' corneal dystrophy in Korean patients

Q455V mutation in COL8A2 is associated with Fuchs' corneal dystrophy in Korean patients

Reprogramming towards anabolism impedes degeneration in a preclinical model of retinitis pigmentosa

Two specific mutations are prevalent causes of recessive retinitis pigmentosa in North American patients of Jewish ancestry

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