<i>TULP1</i>Mutations Causing Early-Onset Retinal Degeneration: Preserved but Insensitive Macular Cones

Jacobson, Samuel G.; Cideciyan, Artur V.; Huang, Wei; Sumaroka, Alexander; Román, Alejandro J.; Schwartz, Sharon; Luo, Xunda; Sheplock, Rebecca; Dauber, Joanna M.; Świder, Małgorzata; Stone, Edwin M.

doi:10.1167/iovs.14-14570

Cited by 42 publications

(40 citation statements)

References 69 publications

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“…S À was measured in NPHP5-LCA patients. The structure-function data from the different genotypes were plotted, and we applied a simple linear model which has been used to describe this relationship in various retinal degenerations (21)(22)(23)(24). The results indicated that central disease due to BBS1, USH2A and RPGR mutations behaved similarly and like pure photoreceptor degenerations.…”

Section: Resultsmentioning

confidence: 99%

“…Dashed lines indicate region of uncertainty defined as translation of the normal variability along the idealized model of a pure photoreceptor degeneration. Results in patients with BBS1 (n ¼ 6), USH2A (n ¼ 7) and RPGR (n ¼ 16) mutations [modified from (21,24,46,47); Supplementary Table S1] are shown with gray symbols; the values fall inside predicted limits of the model. LCA patients with NPHP5 and CEP290 mutations (red and pink triangles) show better structure than predicted by the model.…”

Section: Resultsmentioning

confidence: 99%

“…Overlapping, non-averaged, 9 mm-length scans through the fovea were used to study the retina, and were analyzed with custom programs (MatLab 7.5; MathWorks, Natick, MA). For the outer retinal sublaminae, signal peak assignments were based on our previously published work (21,24,46,47). Foveal ONL and distal substructure thicknesses were measured from three OCT scans through the fovea obtained at the same visit in the NPHP5-LCA patients, and compared with measurements in groups of patients with four other genotypes.…”

Section: Optical Coherence Tomography (Oct) Imaging and Analysesmentioning

confidence: 99%

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Overlap of abnormal photoreceptor development and progressive degeneration in Leber congenital amaurosis caused byNPHP5mutation

et al. 2016

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Ciliary defects can result in severe disorders called ciliopathies. Mutations in NPHP5 cause a ciliopathy characterized by severe childhood onset retinal blindness, Leber congenital amaurosis (LCA), and renal disease. Using the canine NPHP5-LCA model we compared human and canine retinal phenotypes, and examined the early stages of photoreceptor development and degeneration, the kinetics of photoreceptor loss, the progression of degeneration and the expression profiles of selected genes. NPHP5-mutant dogs recapitulate the human phenotype of very early loss of rods, and relative retention of the central retinal cone photoreceptors that lack function. In mutant dogs, rod and cone photoreceptors have a sensory cilium, but develop and function abnormally and then rapidly degenerate; L/M cones are more severely affected than S-cones. The lack of outer segments in mutant cones indicates a ciliary dysfunction. Genes expressed in mutant rod or both rod and cone photoreceptors show significant downregulation, while those expressed only in cones are unchanged. Many genes in celldeath and -survival pathways also are downregulated. The canine disease is a non-syndromic LCA-ciliopathy, with normal renal structures and no CNS abnormalities. Our results identify the critical time points in the pathogenesis of the photoreceptor disease, and bring us closer to defining a potential time window for testing novel therapies for translation to patients. †

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Optical Coherence Tomography (Oct) Imaging and Analysesmentioning

confidence: 99%

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Overlap of abnormal photoreceptor development and progressive degeneration in Leber congenital amaurosis caused byNPHP5mutation

et al. 2016

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“…21,31,32 Retinal and subretinal features were imaged with 820-nm near-infrared (NIR) light in the reflectance (REF) mode. Health of the RPE was estimated with a reducedilluminance autofluorescence imaging (RAFI) method using 790-nm NIR excitation and 488-nm short-wavelength (SW) excitation.…”

Section: Imaging Studiesmentioning

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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“…In these regions, the critique that ONL can be contaminated by HFL reflections is less an issue. 39,40 There is a well-studied relationship of structure to rod as well as cone function from many studies in a number of IRDs, 19,25,37,41,42 and it would seem valuable to have such information to complement that from the EZ line extent. Also worth studying would be why there is measurable function eccentric to the end of the EZ line.…”

Section: Discussionmentioning

confidence: 99%

Outer Retinal Changes Including the Ellipsoid Zone Band in Usher Syndrome 1B due toMYO7AMutations

Sumaroka

Matsui

Cideciyan

et al. 2016

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. To study transition zones from normal to abnormal retina in Usher syndrome IB (USH1B) caused by myosin 7A (MYO7A) mutations. METHODS.Optical coherence tomography (OCT) scattering layers in outer retina were segmented in patients (n ¼ 16, ages 2-42; eight patients had serial data, average interval 4.5 years) to quantify outer nuclear layer (ONL) and outer segments (OS) as well as the locus of EZ (ellipsoid zone) edge and its extent from the fovea. Static perimetry was measured under dark-adapted (DA) and light-adapted (LA) conditions. RESULTS.Ellipsoid zone edge in USH1B-MYO7A could be located up to 238 from the fovea. Ellipsoid zone extent constricted at a rate of 0.518/year with slower rates at smaller eccentricities. A well-defined EZ line could be associated with normal or abnormal ONL and/ or OS thickness; detectable ONL extended well beyond EZ edge. At the EZ edge, the local slope of LA sensitivity loss was 2.6 (61.7) dB/deg for central transition zones. At greater eccentricities, the local slope of cone sensitivity loss was shallower (1.1 6 0.4 dB/deg for LA) than that of rod sensitivity loss (2.8 6 1.2 dB/deg for DA).CONCLUSIONS. In USH1B-MYO7A, constriction rate of EZ extent depends on the initial eccentricity of the transition. Ellipsoid zone edges in the macula correspond to large local changes in cone vision, but extramacular EZ edges show more pronounced losses on rodbased vision tests. It is advisable to use not only the EZ line but also other structural and functional parameters for estimating natural history of disease and possible therapeutic effects in future clinical trials of USH1B-MYO7A.

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TULP1Mutations Causing Early-Onset Retinal Degeneration: Preserved but Insensitive Macular Cones

Cited by 42 publications

References 69 publications

Overlap of abnormal photoreceptor development and progressive degeneration in Leber congenital amaurosis caused byNPHP5mutation

Overlap of abnormal photoreceptor development and progressive degeneration in Leber congenital amaurosis caused byNPHP5mutation

Molecular Heterogeneity Within the Clinical Diagnosis of Pericentral Retinal Degeneration

Outer Retinal Changes Including the Ellipsoid Zone Band in Usher Syndrome 1B due toMYO7AMutations

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