Expanding the phenotypic spectrum in RDH12-associated retinal disease

Scott, Hilary; Place, Emily; Ferenchak, Kevin; Zampaglione, Erin; Wagner, Naomi E.; Chao, Katherine R.; Navarro-Gómez, Daniel; Mukai, Sonoyo; Huckfeldt, Rachel M.; Pierce, Eric A.; Bujakowska, Kinga

doi:10.1101/mcs.a004754

Cited by 20 publications

(17 citation statements)

References 45 publications

(69 reference statements)

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“…Since the advent of next-generation sequencing techniques, LCA-related genes, such as CRX or RDH12, have been unexpectedly linked to isolated maculopathies [ 3 , 4 , 5 , 6 ]. Tsang et al reported the first cases of macular dystrophy with bi-allelic pathogenic variants in CRB1 [ 7 ].…”

Section: Introductionmentioning

confidence: 99%

CRB1-Related Retinal Dystrophies in a Cohort of 50 Patients: A Reappraisal in the Light of Specific Müller Cell and Photoreceptor CRB1 Isoforms

Mairot¹,

Smirnov

Bocquet

et al. 2021

IJMS

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Pathogenic variants in CRB1 lead to diverse recessive retinal disorders from severe Leber congenital amaurosis to isolated macular dystrophy. Until recently, no clear phenotype-genotype correlation and no appropriate mouse models existed. Herein, we reappraise the phenotype-genotype correlation of 50 patients with regards to the recently identified CRB1 isoforms: a canonical long isoform A localized in Müller cells (12 exons) and a short isoform B predominant in photoreceptors (7 exons). Twenty-eight patients with early onset retinal dystrophy (EORD) consistently had a severe Müller impairment, with variable impact on the photoreceptors, regardless of isoform B expression. Among them, two patients expressing wild type isoform B carried one variant in exon 12, which specifically damaged intracellular protein interactions in Müller cells. Thirteen retinitis pigmentosa patients had mainly missense variants in laminin G-like domains and expressed at least 50% of isoform A. Eight patients with the c.498_506del variant had macular dystrophy. In one family homozygous for the c.1562C>T variant, the brother had EORD and the sister macular dystrophy. In contrast with the mouse model, these data highlight the key role of Müller cells in the severity of CRB1-related dystrophies in humans, which should be taken into consideration for future clinical trials.

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Section: Introductionmentioning

confidence: 99%

CRB1-Related Retinal Dystrophies in a Cohort of 50 Patients: A Reappraisal in the Light of Specific Müller Cell and Photoreceptor CRB1 Isoforms

Mairot¹,

Smirnov

Bocquet

et al. 2021

IJMS

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“…Clinical evaluation was performed by experienced ophthalmologists according to previously published protocols and included functional and structural assessments. 13–16…”

Section: Methodsmentioning

confidence: 99%

Early onset non-syndromic retinal degeneration due to variants in INPP5E: phenotypic expansion of the ciliary gene previously associated with Joubert syndrome

Sangermano

Deitch

Peter

et al. 2020

Preprint

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Purpose: Pathogenic variants in INPP5E cause Joubert syndrome, a systemic disorder that can manifest with retinal degeneration among other clinical features. We aimed to evaluate the role of INPP5E variants in non-syndromic inherited retinal degenerations (IRDs) of varying severity. Methods: Targeted or genome sequencing were performed in 12 unrelated non-syndromic IRD families from multiple research hospitals. Detailed clinical examination was conducted in all probands. The impact of new likely pathogenic variants was modeled on a tertiary INPP5E protein structure and all the new and published variants were analyzed for their deleteriousness and phenotypic correlation. Results: Fourteen INPP5E rare alleles were detected, 12 of which were novel. Retinal degeneration in all 12 probands was clinically distinguishable on the basis of onset and severity into Leber congenital amaurosis (n=4) and a milder, later-onset rod-cone dystrophy (n=8). Two probands showed mild ciliopathy features that resolved in childhood. Analysis of the combined impact of both alleles in syndromic and non-syndromic INPP5E patients did not reveal clear genotype-phenotype correlation, suggesting involvement of genetic modifiers. Conclusions: The study expands the phenotypic spectrum of disorders due to pathogenic variants in INPP5E and describes a new disease association with previously underdiagnosed forms of early-onset non-syndromic IRD.

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“…A phenotypic feature of RDH12 retinopathy is sparing of the peripapillary region [149,151,153] (Figure 6), pathognomonic of ABCA4-retinopathy. Mutations in RDH12 gene have been found in patients with autosomal recessive retinitis RP, cone-rod dystrophy as well as macular dystrophy [154]. Interestingly, pathogenic variants in RDH8 have not yet been linked to any retinal disease.…”

Section: Retinopathy Due To Pathogenic Variants In Rdh8 or Rdh12mentioning

confidence: 99%

The Role of Vitamin A in Retinal Diseases

Sajovic

Meglič

Glavač

et al. 2022

IJMS

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Vitamin A is an essential fat-soluble vitamin that occurs in various chemical forms. It is essential for several physiological processes. Either hyper- or hypovitaminosis can be harmful. One of the most important vitamin A functions is its involvement in visual phototransduction, where it serves as the crucial part of photopigment, the first molecule in the process of transforming photons of light into electrical signals. In this process, large quantities of vitamin A in the form of 11-cis-retinal are being isomerized to all-trans-retinal and then quickly recycled back to 11-cis-retinal. Complex machinery of transporters and enzymes is involved in this process (i.e., the visual cycle). Any fault in the machinery may not only reduce the efficiency of visual detection but also cause the accumulation of toxic chemicals in the retina. This review provides a comprehensive overview of diseases that are directly or indirectly connected with vitamin A pathways in the retina. It includes the pathophysiological background and clinical presentation of each disease and summarizes the already existing therapeutic and prospective interventions.

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Expanding the phenotypic spectrum in RDH12-associated retinal disease

Cited by 20 publications

References 45 publications

CRB1-Related Retinal Dystrophies in a Cohort of 50 Patients: A Reappraisal in the Light of Specific Müller Cell and Photoreceptor CRB1 Isoforms

CRB1-Related Retinal Dystrophies in a Cohort of 50 Patients: A Reappraisal in the Light of Specific Müller Cell and Photoreceptor CRB1 Isoforms

Early onset non-syndromic retinal degeneration due to variants in INPP5E: phenotypic expansion of the ciliary gene previously associated with Joubert syndrome

The Role of Vitamin A in Retinal Diseases

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