The<i>PROM1</i>Mutation p.R373C Causes an Autosomal Dominant Bull's Eye Maculopathy Associated with Rod, Rod–Cone, and Macular Dystrophy

Michaelides, Michel; Gaillard, Marie-Claire; Escher, Pascal; Tiab, Leila; Bedell, Matthew; Borruat, François‐Xavier; Barthelmes, Daniel; Carmona, Ruben; Zhang, Kang; White, Edward T.; McClements, Michelle E.; Robson, Anthony G.; Holder, Graham E.; Bradshaw, Keith; Hunt, David M.; Webster, Andrew R.; Moore, Anthony T.; Schorderet, Daniel F.; Munier, Francis L.

doi:10.1167/iovs.09-4561

Cited by 98 publications

(112 citation statements)

References 29 publications

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“…[1][2][3][4] Mutations in PROM1 have been shown to result in retinitis pigmentosa, 5,6 macular degeneration 7,8 and cone-rod dystrophy. 9 PROM1 encodes prominin-1, a 5-transmembrane glycoprotein also known as CD133 and AC133. CD133 was originally identified as a cell surface antigen present on hematopoietic stem cells and on early progenitor cells in the bone marrow, including endothelial progenitor cells (EPCs).…”

Section: Introductionmentioning

confidence: 99%

Extended extraocular phenotype of PROM1 mutation in kindreds with known autosomal dominant macular dystrophy

et al. 2010

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Mutations in prominin 1 (PROM1) have been shown to result in retinitis pigmentosa, macular degeneration and cone-rod dystrophy. Because of the putative role of PROM1 in hippocampal neurogenesis, we examined two kindreds with the same R373C PROM1 missense mutation using our established paradigm to study brain structure and function. As the protein encoded by PROM1, known as CD133, is used to identify stem/progenitor cells that can be found in peripheral blood and reflect endothelial reparatory mechanisms, other parameters were subsequently examined that included measures of vascular function, endothelial function and angiogenic capacity. We found that aspects of endothelial function assayed ex vivo were abnormal in patients with the R373C PROM1 mutation, with impaired adhesion capacity and higher levels of cellular damage. We also noted renal infections, haematuria and recurrent miscarriages possibly reflecting consequences of abnormal tubular modelling. Further studies are needed to confirm these findings.

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Section: Introductionmentioning

confidence: 99%

Extended extraocular phenotype of PROM1 mutation in kindreds with known autosomal dominant macular dystrophy

et al. 2010

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“…Nevertheless, it cannot be excluded that the phenotype in this family is explained by two recessive PROM1 mutations, 23,24 rather than a single dominant one. 25,26 Among the unsolved autosomal recessive or sporadic cases, amino acid alterations often were bioinformatically predicted to be polymorphisms. Published data was evaluated to verify these predictions.…”

Section: Discussionmentioning

confidence: 99%

Panel-based next generation sequencing as a reliable and efficient technique to detect mutations in unselected patients with retinal dystrophies

et al. 2013

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Hereditary retinal dystrophies (RD) constitute a group of blinding diseases that are characterized by clinical variability and pronounced genetic heterogeneity. The different forms of RD can be caused by mutations in 4100 genes, including 41600 exons. Consequently, next generation sequencing (NGS) technologies are among the most promising approaches to identify mutations in RD. So far, NGS is not routinely used in gene diagnostics. We developed a diagnostic NGS pipeline to identify mutations in 170 genetically and clinically unselected RD patients. NGS was applied to 105 RD-associated genes. Underrepresented regions were examined by Sanger sequencing. The NGS approach was successfully established using cases with known sequence alterations. Depending on the initial clinical diagnosis, we identified likely causative mutations in 55% of retinitis pigmentosa and 80% of Bardet-Biedl or Usher syndrome cases. Seventy-one novel mutations in 40 genes were newly associated with RD. The genes USH2A, EYS, ABCA4, and RHO were more frequently affected than others. Occasionally, cases carried mutations in more than one RD-associated gene. In addition, we found possible dominant de-novo mutations in cases with sporadic RD, which implies consequences for counseling of patients and families. NGS-based mutation analyses are reliable and cost-efficient approaches in gene diagnostics of genetically heterogeneous diseases like RD.

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“…Mutations in PROM1 are described as causing RP, macular dystrophy, and cone-rod degeneration and both ad and ar inheritance patterns are reported. [60][61][62] PROM1 has been suggested to have a role in photoreceptor disk morphogenesis. 60 The remaining three genes identified in our PRD cohort have been associated only with ar disease.…”

Section: Molecular Heterogeneity In Pericentral Rpmentioning

confidence: 99%

“…For example, RDS, CRX, PROM1, and ABCA4 have all been associated with RP, macular dystrophy and cone-rod dystrophy. 53,54,61,62,69,70 RHO is associated with different patterns of disease, from early retina-wide rod loss to initially delimited altitudinal or sectoral defects. 29,71 A pericentral disease distribution has been reported in a patient with a RHO T58R mutation (Fig.…”

Section: Molecular Heterogeneity In Pericentral Rpmentioning

confidence: 99%

Molecular Heterogeneity Within the Clinical Diagnosis of Pericentral Retinal Degeneration

Matsui

Cideciyan

Schwartz

et al. 2015

Invest. Ophthalmol. Vis. Sci.

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METHODS. Patients were screened for an annular ring scotoma ranging from 38 to 408 (n ¼ 28, ages 24-71) with kinetic perimetry. All patients had pigmentary retinopathy in the region of the dysfunction. Further studies included cross-sectional and en face imaging, static chromatic perimetry, and electroretinography. Molecular screening was performed.RESULTS. Genotypes of 14 of 28 PRD patients were identified: There were mutations in eight different genes previously associated with autosomal dominant or autosomal recessive RDs. Kinetic fields monitored in some patients over years to more than a decade could be stable or show increased extent of the scotoma. Electroretinograms were recordable but with different severities of dysfunction. Patterns of photoreceptor outer nuclear layer (ONL) loss corresponded to the distribution of visual dysfunction. Outer nuclear layer thickness topography and en face imaging indicated that the greatest disease expression was in the area of known highest rod photoreceptor density.CONCLUSIONS. Molecular heterogeneity was a feature of the PRD phenotype. Many of the molecular causes were also associated with other phenotypes, such as maculopathies, typical retinitis pigmentosa (RP) and cone-rod dystrophy. The pericentral pattern of retinal degeneration is thus confirmed to be an uncommon phenotype of many different genotypes rather than a distinct disease entity.

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ThePROM1Mutation p.R373C Causes an Autosomal Dominant Bull's Eye Maculopathy Associated with Rod, Rod–Cone, and Macular Dystrophy

Cited by 98 publications

References 29 publications

Extended extraocular phenotype of PROM1 mutation in kindreds with known autosomal dominant macular dystrophy

Extended extraocular phenotype of PROM1 mutation in kindreds with known autosomal dominant macular dystrophy

Panel-based next generation sequencing as a reliable and efficient technique to detect mutations in unselected patients with retinal dystrophies

Molecular Heterogeneity Within the Clinical Diagnosis of Pericentral Retinal Degeneration

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