The Effect on Retinal Structure and Function of 15 Specific <i>ABCA4</i> Mutations: A Detailed Examination of 82 Hemizygous Patients

Fakin, Ana; Robson, Anthony G.; Chiang, John; Fujinami, Kaoru; Moore, Anthony T.; Michaelides, Michel; Holder, Graham E.; Webster, Andrew R.

doi:10.1167/iovs.16-20446

Cited by 41 publications

(78 citation statements)

References 36 publications

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“…S3), although the BVCA was 0.05 logMAR units bilaterally. This may be because the preserved foveal region was too small to evoke normal ERGs, and we suggest that the etiology of our three cases was similar to that reported by Kondo et al 44 A sparing of the fovea is commonly observed in different types of macular diseases, such as in ABCA4-and PRPH2associated retinopathies, 17,18,43,[45][46][47][48] mitochondrial retinal dystrophy, 49 macular dystrophy with CRB1 mutation, 50 and agerelated macular degeneration. [51][52][53][54] The explanations for the physiologic and anatomic sparing of the fovea have been presented in many publications.…”

Section: Discussionsupporting

confidence: 80%

“…These FAF abnormalities, however, were much less severe than in other macular dystrophies. 2,7,10,11,13,15,17,21,23,24,[41][42][43] Also, a hypo-AF, which indicates long-term RPE dysfunction, was not observed in any of the eyes. By comparing the FAF of a severe case with CRX-retinopathy that had severe photoreceptor and RPE degeneration at the macula, we would strongly suggest that patients with POC1B-associated retinopathy had never had severe hyporeflectivity, as found in patients with CRX-retinopathy.…”

Section: Discussionmentioning

confidence: 82%

“…Thus, the pathologic mechanism for the foveal sparing may differ between the cases with POC1B mutations and other macular dystrophies. 17,18,43,[45][46][47][48][49][50][51][52][53][54] Although the numbers of the eyes with foveal sparing are limited, further investigations to determine whether there is a significant association between the genotype and RPE findings (i.e., the presence or absence of RPE atrophy) in a large cohort with foveal sparing could determine the mechanism of the foveal sparing.…”

Section: Discussionmentioning

confidence: 99%

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Phenotypical Characteristics ofPOC1B-Associated Retinopathy in Japanese Cohort: Cone Dystrophy With Normal Funduscopic Appearance

Kameya

Fujinami

Ueno

et al. 2019

Invest. Ophthalmol. Vis. Sci.

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Citation: Kameya S, Fujinami K, Ueno S, et al. Phenotypical characteristics of POC1B-associated retinopathy in Japanese cohort: cone dystrophy with normal funduscopic appearance. Invest Ophthalmol Vis Sci. 2019;60:3432-3446. https://doi.org/ 10.1167/iovs.19-26650 PURPOSE. Cone/cone-rod dystrophy is a large group of retinal disorders with both phonotypic and genetic heterogeneity. The purpose of this study was to characterize the phenotype of eight patients from seven families harboring POC1B mutations in a cohort of the Japan Eye Genetics Consortium (JEGC). METHODS.Whole-exome sequencing with targeted analyses identified homozygous or compound heterozygous mutations of the POC1B gene in 7 of 548 families in the JEGC database. Ophthalmologic examinations including the best-corrected visual acuity, perimetry, fundus photography, fundus autofluorescence imaging, optical coherence tomography, and full-field and multifocal electroretinography (ERGs) were performed.RESULTS. There were four men and four women whose median age at the onset of symptoms was 15.6 years (range, 6-23 years) and that at the time of examination was 40.3 years (range, 22-67 years). The best-corrected visual acuity ranged from À0.08 to 1.52 logMAR units. The funduscopic appearance was normal in all the cases except in one case with faint mottling in the fovea. Optical coherence tomography revealed an absence of the interdigitation zone and blurred ellipsoid zone in the posterior pole, but the foveal structures were preserved in three cases. The full-field photopic ERGs were reduced or extinguished with normal scotopic responses. The central responses of the multifocal ERGs were preserved in two cases. The diagnosis was either generalized cone dystrophy in five cases or cone dystrophy with foveal sparing in three cases.CONCLUSIONS. Generalized or peripheral cone dystrophy with normal funduscopic appearance is the representative phenotype of POC1B-associated retinopathy in our cohort.Whole-exome sequencing and targeted sequence analyses of the 301 retinal disease-associated genes (including genes of Retnet; https://sph.uth.edu/retnet/, in the public domain) were done according to the published protocol of the NISO. 35 Paired-end sequence library construction and exome capturing Downloaded from iovs.arvojournals.org on 07/08/2020 FIGURE 8. Horizontal and vertical OCT images of the left eye of patient 1 recorded at the age 35 years (A) and 39 years (B).Longitudinal reflectivity profiles at the fovea are shown below the OCT images. EZ and IZ are preserved in the fovea at the age 35 years but they are blurred at the age of 39 years. The reflectivity profiles show small peaks of IZ at the age 35 years but not at 39 years. The reflectance intensity of the IZ relative to the RPE was 0.82 at the age 35 years and 0.63 at the age 39 years. The reflectance intensity of the EZ relative to the RPE was 0.86 at the age 35 years and 0.77 at the age 39 years. The reflectivity was averaged in width as indicated by the yellow lines. ILM, internal limiting membra...

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Section: Discussionsupporting

confidence: 80%

Section: Discussionmentioning

confidence: 82%

Section: Discussionmentioning

confidence: 99%

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Phenotypical Characteristics ofPOC1B-Associated Retinopathy in Japanese Cohort: Cone Dystrophy With Normal Funduscopic Appearance

Kameya

Fujinami

Ueno

et al. 2019

Invest. Ophthalmol. Vis. Sci.

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“…The age of onset for individuals homozygous for this variant ranges from 10 to 26 years with an average age of 19 yr (Fingert, Eliason et al 2006, Cideciyan, Swider et al 2009, Hwang, Zernant et al 2009, Tanna, Strauss et al 2017. This age of onset is consistent with the moderate disease classification presented here and the moderate classification based on clinical findings (Fakin, Robson et al 2016). When this mutation is in trans with the S1696N mutation, reported here to be a mild Class 3 mutation, then the age of onset is increased to 45 yr supporting our Class 3 designation of the S1696N variant (Hwang, Zernant et al 2009).…”

Section: Discussionsupporting

confidence: 86%

Pathogenic Mechanisms Underlying Stargardt Macular Degeneration Linked to Mutations in the Transmembrane Domains of ABCA4

Garces

Scortecci

Molday

2020

Preprint

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ABCA4 is an ATP-binding cassette (ABC) transporter predominantly expressed in photoreceptors where it transports the substrate N-retinylidene-phosphatidylethanolamine across disc membranes thereby facilitating the clearance of retinal compounds from photoreceptor outer segments. Loss of function mutations in ABCA4 cause the accumulation of bisretinoids leading to Stargardt disease (STGD1) and other retinopathies. In this study, we examined the expression and functional properties of ABCA4 harboring disease-causing missense mutations in the two transmembrane domains (TMDs) of ABCA4. Our results indicate that these mutations lead to protein misfolding, loss in substrate binding, decreased ATPase activity or a combination of these properties. Additionally, we identified an arginine (R653) in transmembrane segment 2 of ABCA4 as a residue essential for substrate binding and substrate-stimulated ATPase activity. The expression and functional activity of the TMD variants correlate well with the severity of STGD1. Our studies provide a basis for developing and evaluating novel treatments for STGD1.

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“…Thus, some of the asymptomatic family members without detailed examinations could have been misclassified to be normal although other factors such as ethnic and environmental differences in the presence of photoreceptor abnormality should be considered to explain the low penetrance in the other studies. 9 A sparing of the fovea is commonly observed in different types of macular diseases, such as in ABCA4-and PRPH2related retinopathies, [27][28][29][30][31][32][33] mitochondrial retinal dystrophy, 34 macular dystrophy with CRB1 mutation, 35 and age-related macular degeneration. [36][37][38][39] The explanations for the physiologic and anatomic sparing of the fovea have been presented in many publications.…”

Section: Discussionmentioning

confidence: 99%

Parafoveal Photoreceptor Abnormalities in Asymptomatic Patients With RP1L1 Mutations in Families With Occult Macular Dystrophy

Kato

Hanazono

Fujinami

et al. 2017

Invest. Ophthalmol. Vis. Sci.

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The Effect on Retinal Structure and Function of 15 Specific ABCA4 Mutations: A Detailed Examination of 82 Hemizygous Patients

Cited by 41 publications

References 36 publications

Phenotypical Characteristics ofPOC1B-Associated Retinopathy in Japanese Cohort: Cone Dystrophy With Normal Funduscopic Appearance

Phenotypical Characteristics ofPOC1B-Associated Retinopathy in Japanese Cohort: Cone Dystrophy With Normal Funduscopic Appearance

Pathogenic Mechanisms Underlying Stargardt Macular Degeneration Linked to Mutations in the Transmembrane Domains of ABCA4

Parafoveal Photoreceptor Abnormalities in Asymptomatic Patients With RP1L1 Mutations in Families With Occult Macular Dystrophy

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