Accessory heterozygous mutations in cone photoreceptor CNGA3 exacerbate CNG channel–associated retinopathy

Burkard, Markus; Kohl, Susanne; Krätzig, Timm; Tanimoto, Naoyuki; Brennenstuhl, Christina; Bausch, Anne E.; Junger, Katrin; Reuter, Peggy; Sothilingam, Vithiyanjali; Beck, Susanne; Huber, Günter L.; Ding, Xi; Mayer, Achim; Baumann, Britta; Weisschuh, Nicole; Zobor, Ditta; Hahn, Gesa Astrid; Kellner, Ulrich; Venturelli, Sascha; Becirovic, Elvir; Issa, Peter Charbel; Koenekoop, Robert K.; Rudolph, Günther; Heckenlively, John R.; Sieving, Paul A.; Weleber, Richard G.; Hamel, Christian; Zong, Xin; Biel, Martin; Łukowski, Robert; Seeliger, M. W.; Michalakis, Stylianos; Wissinger, Bernd; Ruth, Peter

doi:10.1172/jci96098

Cited by 26 publications

(29 citation statements)

References 86 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Folding, intracellular processing, and transport are thought to be impaired [29]. The effects of individual CNGA3 amino acid substitutions on CNG channel function have mainly been studied in vitro [21,[30][31][32][33][34][35][36][37][38][39][40][41][42][43][44][45][46]. Some insights have been gained, but the exact mechanisms linking CNGA3 amino acid substitutions to cone photoreceptor dysfunction and eventual degeneration are still not well understood.…”

Section: The Mutation Landscape In Cnga3and Cngb3-linked Achromatopsiamentioning

confidence: 99%

Achromatopsia: Genetics and Gene Therapy

et al. 2021

Self Cite

View full text Add to dashboard Cite

Achromatopsia (ACHM), also known as rod monochromatism or total color blindness, is an autosomal recessively inherited retinal disorder that affects the cones of the retina, the type of photoreceptors responsible for high-acuity daylight vision. ACHM is caused by pathogenic variants in one of six cone photoreceptor-expressed genes. These mutations result in a functional loss and a slow progressive degeneration of cone photoreceptors. The loss of cone photoreceptor function manifests at birth or early in childhood and results in decreased visual acuity, lack of color discrimination, abnormal intolerance to light (photophobia), and rapid involuntary eye movement (nystagmus). Up to 90% of patients with ACHM carry mutations in CNGA3 or CNGB3, which are the genes encoding the alpha and beta subunits of the cone cyclic nucleotide-gated (CNG) channel, respectively. No authorized therapy for ACHM exists, but research activities have intensified over the past decade and have led to several preclinical gene therapy studies that have shown functional and morphological improvements in animal models of ACHM. These encouraging preclinical data helped advance multiple gene therapy programs for CNGA3-and CNGB3-linked ACHM into the clinical phase. Here, we provide an overview of the genetic and molecular basis of ACHM, summarize the gene therapy-related research activities, and provide an outlook for their clinical application. Key PointsAchromatopsia (ACHM) is caused by mutations in one of six autosomal recessive genes and affects all aspects of daylight vision.No therapy for ACHM has yet been approved, but several preclinical studies provided proof of concept for adeno-associated virus gene therapy.Five clinical gene therapy trials are currently underway for CNGA3-and CNGB3-related ACHM.

show abstract

Section: The Mutation Landscape In Cnga3and Cngb3-linked Achromatopsiamentioning

confidence: 99%

Achromatopsia: Genetics and Gene Therapy

et al. 2021

Self Cite

View full text Add to dashboard Cite

show abstract

“…PDE6H (MIM 601190) is associated with autosomal recessive congenital cone dystrophy (MIM 610024) ( Kohl et al, 2012 ; Pedurupillay et al, 2016 ). While a second allele was not identified, it is conceivable that this case of OT is caused by a non-coding variant altering expression of PDE6H , or a variant in another congenital cone dystrophy gene acting in a digenic manner, as reported in patients with achromatopsia ( Burkard et al, 2018 ). More recently, the advent of whole genome sequencing along with RNA-seq has been very helpful in identification of a second pathogenic allele in genes causing achromatopsia, mostly deep intronic variants causing aberrant splice events ( Burkard et al, 2018 ; Weisschuh et al, 2020 ).…”

Section: Discussionmentioning

confidence: 92%

Persistent Dark Cones in Oligocone Trichromacy Revealed by Multimodal Adaptive Optics Ophthalmoscopy

Liu

Flynn

et al. 2021

Front. Aging Neurosci.

View full text Add to dashboard Cite

Dark cone photoreceptors, defined as those with diminished or absent reflectivity when observed with adaptive optics (AO) ophthalmoscopy, are increasingly reported in retinal disorders. However, their structural and functional impact remain unclear. Here, we report a 3-year longitudinal study on a patient with oligocone trichromacy (OT) who presented with persistent, widespread dark cones within and near the macula. Diminished electroretinogram (ERG) cone but normal ERG rod responses together with normal color vision confirmed the OT diagnosis. In addition, the patient had normal to near normal visual acuity and retinal sensitivity. Occasional dark gaps in the photoreceptor layer were observed on optical coherence tomography, in agreement with reflectance AO scanning light ophthalmoscopy, which revealed that over 50% of the cones in the fovea were dark, increasing to 74% at 10° eccentricity. In addition, the cone density was 78% lower than normal histologic value at the fovea, and 20–40% lower at eccentricities of 5–15°. Interestingly, color vision testing was near normal at locations where cones were predominantly dark. These findings illustrate how a retina with predominant dark cones that persist over at least 3 years can support near normal central retinal function. Furthermore, this study adds to the growing evidence that cones can continue to survive under non-ideal conditions.

show abstract

“…Cone retinopathy-patients in Tubingen were found to harbor digenic-triallelic mutations in CNGB3/A3. Around 62.5% of the patients who had either homozygous (R403Q) or compound heterozygous mutations in CNGB3 (R403Q+other mutation) also harbored an additional heterozygous mutation in CNGA3 [214]. The CNGA3 mutation was found to be pathogenic with a severe phenotype as compared to the patients who had only monogenic CNGB3 mutations suggesting a hypomorphic effect of CNGB3-R403Q mutation.…”

Section: Cnga3 and Cngb3 (Cone Specific Cyclic Nucleotide-gated Channmentioning

confidence: 95%

“…The animal studies further supported the role of digenic triallelic inheritance in cone retinopathies. The mouse model of digenic triallelic (Cnga3 +/-Cngb3 R403Q/R403Q ) nature exhibited a severe disease phenotype as compared to Cngb3 R403Q/R403Q mice as demonstrated by the loss of cone photoreceptor function and structural integrity [214].…”

Section: Cnga3 and Cngb3 (Cone Specific Cyclic Nucleotide-gated Channmentioning

confidence: 99%

Sensing through Non-Sensing Ocular Ion Channels

Kabra

Pattnaik

2020

IJMS

View full text Add to dashboard Cite

Ion channels are membrane-spanning integral proteins expressed in multiple organs, including the eye. In the eye, ion channels are involved in various physiological processes, like signal transmission and visual processing. A wide range of mutations have been reported in the corresponding genes and their interacting subunit coding genes, which contribute significantly to an array of blindness, termed ocular channelopathies. These mutations result in either a loss- or gain-of channel functions affecting the structure, assembly, trafficking, and localization of channel proteins. A dominant-negative effect is caused in a few channels formed by the assembly of several subunits that exist as homo- or heteromeric proteins. Here, we review the role of different mutations in switching a “sensing” ion channel to “non-sensing,” leading to ocular channelopathies like Leber’s congenital amaurosis 16 (LCA16), cone dystrophy, congenital stationary night blindness (CSNB), achromatopsia, bestrophinopathies, retinitis pigmentosa, etc. We also discuss the various in vitro and in vivo disease models available to investigate the impact of mutations on channel properties, to dissect the disease mechanism, and understand the pathophysiology. Innovating the potential pharmacological and therapeutic approaches and their efficient delivery to the eye for reversing a “non-sensing” channel to “sensing” would be life-changing.

show abstract

Accessory heterozygous mutations in cone photoreceptor CNGA3 exacerbate CNG channel–associated retinopathy

Cited by 26 publications

References 86 publications

Achromatopsia: Genetics and Gene Therapy

Achromatopsia: Genetics and Gene Therapy

Persistent Dark Cones in Oligocone Trichromacy Revealed by Multimodal Adaptive Optics Ophthalmoscopy

Sensing through Non-Sensing Ocular Ion Channels

Contact Info

Product

Resources

About