Biallelic Mutations in<i>CRB1</i>Underlie Autosomal Recessive Familial Foveal Retinoschisis

Vincent, Ajoy; Ng, Judith; Gerth‐Kahlert, Christina; Tavares, Erika; Maynes, Jason T.; Wright, Thomas; Tiwari, Anjali; Tumber, Anupreet; Li, Shuning; Hanson, James V M; Bahr, Angela; MacDonald, Heather; Bähr, Luzy; Westall, Carol A.; Berger, Wolfgang; Cremers, Frans P.M.; Hollander, Anneke I. den; Hèon, Elise

doi:10.1167/iovs.15-18281

Cited by 34 publications

(38 citation statements)

References 49 publications

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“…Genetic testing identified two disease-causing variants in all patients. Six shared a rare, single allele resulting in an inframe deletion of three amino acids (NM_201253.2: c.498_506delAATTGATGG, NP_957705.1:p.(Ile167_Gly169del)) previously associated with disease (rs398124615) [9, 10, 26, 27]. The trans -acting variants in each case were predicted to result in either a missense (p. (Cys195Phe), p.(Arg764Cys) or p.(Pro1381Thr)) or a premature termination codon (p.(Cys896Ter), p.(Ser478ProfsTer24)) (Table 1).…”

Section: Resultsmentioning

confidence: 99%

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A clinical and molecular characterisation of CRB1-associated maculopathy

et al. 2018

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To date, over 150 disease-associated variants in CRB1 have been described, resulting in a range of retinal disease phenotypes including Leber congenital amaurosis and retinitis pigmentosa. Despite this, no genotype–phenotype correlations are currently recognised. We performed a retrospective review of electronic patient records to identify patients with macular dystrophy due to bi-allelic variants in CRB1. In total, seven unrelated individuals were identified. The median age at presentation was 21 years, with a median acuity of 0.55 decimalised Snellen units (IQR = 0.43). The follow-up period ranged from 0 to 19 years (median = 2.0 years), with a median final decimalised Snellen acuity of 0.65 (IQR = 0.70). Fundoscopy revealed only a subtly altered foveal reflex, which evolved into a bull’s-eye pattern of outer retinal atrophy. Optical coherence tomography identified structural changes—intraretinal cysts in the early stages of disease, and later outer retinal atrophy. Genetic testing revealed that one rare allele (c.498_506del, p.(Ile167_Gly169del)) was present in all patients, with one patient being homozygous for the variant and six being heterozygous. In trans with this, one variant recurred twice (p.(Cys896Ter)), while the four remaining alleles were each observed once (p.(Pro1381Thr), p.(Ser478ProfsTer24), p.(Cys195Phe) and p.(Arg764Cys)). These findings show that the rare CRB1 variant, c.498_506del, is strongly associated with localised retinal dysfunction. The clinical findings are much milder than those observed with bi-allelic, loss-of-function variants in CRB1, suggesting this in-frame deletion acts as a hypomorphic allele. This is the most prevalent disease-causing CRB1 variant identified in the non-Asian population to date.

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Section: Resultsmentioning

confidence: 99%

“…Isolated macular disease is a recently identified and rare consequence of variants in CRB1 (Supplementary Table 1) [7–10]. The underlying genotypes are summarised in Supplementary Tables 1 and 2.…”

Section: Discussionmentioning

confidence: 99%

A clinical and molecular characterisation of CRB1-associated maculopathy

et al. 2018

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“…8,21,[25][26][27][28][29] Besides, the macular degeneration such as the isolated macular atrophy, bull's like macular change as well as yellowish flecks deposit around the macular area also have been reported among the CRB1-associated retinopathy patients. 32,[52][53][54] However, there has not been a systematic study to illuminate the CRB1-associated fundus changes because of the limitation of low quantity of cases and few long-term follow-up visit patients. Based on the study's large case series and the long-term follow-up observation, two major kinds of the CRB1-associated fundus changes were identified, including the isolated yellowish geographic macular degeneration without noticeable pigmentation clumps at early stages and macular nummular pigmentation with significant mid-peripheral pigmentation at advanced stages.…”

Section: Discussionmentioning

confidence: 99%

Clinical and Genetic Analysis of 63 Families Demonstrating Early and Advanced Characteristic Fundus as the Signature of CRB1 Mutations

Wang

Sun

Xiao

et al. 2021

American Journal of Ophthalmology

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“…Disease onset can be from early childhood, however, some patients do not exhibit symptoms until after the first decade of life [290][291][292]. Additional CRB1 clinically relevant features include macular atrophy, keratoconus, Coats-like exudative vasculopathy, RP without PPRPE, pigmented paravenous chorioretinal atrophy, and nanophthalmos [288,[293][294][295][296][297].…”

Section: Crb1 and Leber Congenital Amaurosismentioning

confidence: 99%

Retinogenesis of the Human Fetal Retina: An Apical Polarity Perspective

Quinn

Wijnholds

2019

Genes

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The Crumbs complex has prominent roles in the control of apical cell polarity, in the coupling of cell density sensing to downstream cell signaling pathways, and in regulating junctional structures and cell adhesion. The Crumbs complex acts as a conductor orchestrating multiple downstream signaling pathways in epithelial and neuronal tissue development. These pathways lead to the regulation of cell size, cell fate, cell self-renewal, proliferation, differentiation, migration, mitosis, and apoptosis. In retinogenesis, these are all pivotal processes with important roles for the Crumbs complex to maintain proper spatiotemporal cell processes. Loss of Crumbs function in the retina results in loss of the stratified appearance resulting in retinal degeneration and loss of visual function. In this review, we begin by discussing the physiology of vision. We continue by outlining the processes of retinogenesis and how well this is recapitulated between the human fetal retina and human embryonic stem cell (ESC) or induced pluripotent stem cell (iPSC)-derived retinal organoids. Additionally, we discuss the functionality of in utero and preterm human fetal retina and the current level of functionality as detected in human stem cell-derived organoids. We discuss the roles of apical-basal cell polarity in retinogenesis with a focus on Leber congenital amaurosis which leads to blindness shortly after birth. Finally, we discuss Crumbs homolog (CRB)-based gene augmentation.

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Biallelic Mutations inCRB1Underlie Autosomal Recessive Familial Foveal Retinoschisis

Abstract: This is the first report to implicate CRB1 as the underlying cause of FFR. This phenotype forms the mildest end of the spectrum of CRB1-related diseases.

Cited by 34 publications

References 49 publications

A clinical and molecular characterisation of CRB1-associated maculopathy

A clinical and molecular characterisation of CRB1-associated maculopathy

Clinical and Genetic Analysis of 63 Families Demonstrating Early and Advanced Characteristic Fundus as the Signature of CRB1 Mutations

Retinogenesis of the Human Fetal Retina: An Apical Polarity Perspective

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