Segregation of a mutation in CNGB1 encoding the β-subunit of the rod cGMP-gated channel in a family with autosomal recessive retinitis pigmentosa

Bareil, Corinne; Hamel, Christian; Delague, Valérie; Arnaud, B; Demaille, Jacques; Claustres, Mireille

doi:10.1007/s004390100496

Cited by 109 publications

(83 citation statements)

References 27 publications

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“…Recently, RP patients have been identified who carry a point mutation in the CNBD of CNGB1 (Bareil et al, 2001). So far, the functional consequences of this mutation, G993V, which involves a highly conserved residue in the CNG channel family, have not been determined in expression systems.…”

Section: Discussionmentioning

confidence: 99%

“…Alternatively, if the mutant CNGB1 was produced and assembled with CNGA1, it might impair the cGMPdependent activation of the channel. In any case, the observation that RP patients carrying the G993V mutation show no olfactory impairment (Bareil et al, 2001) would tend to suggest that the CNGB1 mutation impact photoreceptors and olfactory receptor neurons differently. …”

Section: Discussionmentioning

confidence: 99%

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Impaired Channel Targeting and Retinal Degeneration in Mice Lacking the Cyclic Nucleotide-Gated Channel Subunit CNGB1

Hüttl¹,

Michalakis²,

Seeliger³

et al. 2005

J. Neurosci.

145

134

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Cyclic nucleotide-gated (CNG) channels are important mediators in the transduction pathways of rod and cone photoreceptors. Native CNG channels are heterotetramers composed of homologous A and B subunits. In heterologous expression systems, B subunits alone cannot form functional CNG channels, but they confer a number of channel properties when coexpressed with A subunits. To investigate the importance of the CNGB subunits in vivo, we deleted the CNGB1 gene in mice. In the absence of CNGB1, only trace amounts of the CNGA1 subunit were found on the rod outer segment. As a consequence, the vast majority of isolated rod photoreceptors in mice lacking CNGB1 (CNGB1 Ϫ/Ϫ ) failed to respond to light. In electroretinograms (ERGs), CNGB1 Ϫ/Ϫ mice showed no rod-mediated responses. The rods also showed a slow-progressing degeneration caused by apoptotic death and concurred by retinal gliosis. Cones were primarily unaffected and showed normal ERG responses up to 6 months, but they started to degenerate in later stages. At the age of ϳ1 year, CNGB1 Ϫ/Ϫ animals were devoid of both rods and cones. Our results show that CNGB1 is a crucial determinant of native CNG channel targeting. As a result of the lack of rod CNG channels, CNGB1 Ϫ/Ϫ mice develop a retinal degeneration that resembles human retinitis pigmentosa.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Impaired Channel Targeting and Retinal Degeneration in Mice Lacking the Cyclic Nucleotide-Gated Channel Subunit CNGB1

Hüttl¹,

Michalakis²,

Seeliger³

et al. 2005

J. Neurosci.

145

134

View full text Add to dashboard Cite

show abstract

“…Defects within the channel-like coding region of the human CNGB1 locus were shown to cause distinct forms of autosomal recessive retinitis pigmentosa (arRP) (Bareil et al, 2001;Kondo et al, 2004). In a large screen of patients with arRP we found a few patients with potential defects in the GARP region of the gene (S.J.P., unpublished results); however, the families analyzed were too small to establish a causal relationship.…”

Section: Journal Of Cell Science 122 (8)mentioning

confidence: 99%

Knockout of GARPs and the β-subunit of the rod cGMP-gated channel disrupts disk morphogenesis and rod outer segment structural integrity

Zhang

Molday

et al. 2009

Journal of Cell Science

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Ion flow into the rod photoreceptor outer segment (ROS) is regulated by a member of the cyclic-nucleotide-gated cation-channel family; this channel consists of two subunit types, α and β. In the rod cells, the Cngb1 locus encodes the channel β-subunit and two related glutamic-acid-rich proteins (GARPs). Despite intensive research, it is still unclear why the β-subunit and GARPs are coexpressed and what function these proteins serve. We hypothesized a role for the proteins in the maintenance of ROS structural integrity. To test this hypothesis, we created a Cngb1 5′-knockout photoreceptor null (Cngb1-X1). Morphologically, ROSs were shorter and, in most rods that were examined, some disks were misaligned, misshapen and abnormally elongated at periods when stratification was still apparent and degeneration was limited. Additionally, a marked reduction in the level of channel α-subunit, guanylate cyclase I (GC1) and ATP-binding cassette transporter (ABCA4) was observed without affecting levels of other ROS proteins, consistent with a requirement for the β-subunit in channel assembly or targeting of select proteins to ROS. Remarkably, phototransduction still occurred when only trace levels of homomeric α-subunit channels were present, although rod sensitivity and response amplitude were both substantially reduced. Our results demonstrate that the β-subunit and GARPs are necessary not only to maintain ROS structural integrity but also for normal disk morphogenesis, and that the β-subunit is required for normal light sensitivity of the rods.

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“…Half of the genes underlying autosomal recessive RP have been identified using this approach, both in consanguineous (Bareil et al 2001;den Hollander et al 2009;Bandah-Rozenfeld et al 2010a,b;Collin et al 2010), and in nonconsanguineous families (den Hollander et al 2007;Collin et al 2008). In brief, a microarray hybridization technique is used to genotype single nucleotide polymorphisms (SNPs) equally spread across the genome.…”

Section: Genetic Linkage Studies and Copy Number Variant Detectionmentioning

confidence: 99%

Genomic Approaches For the Discovery of Genes Mutated in Inherited Retinal Degeneration

Siemiątkowska

Collin

Hollander

et al. 2014

Cold Spring Harbor Perspectives in Medicine

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Correspondence: Frans. Cremers@radboudumc.nl In view of their high degree of genetic heterogeneity, inherited retinal diseases (IRDs) pose a significant challenge for identifying novel genetic causes. Thus far, more than 200 genes have been found to be mutated in IRDs, which together contain causal variants in .80% of the cases. Accurate genetic diagnostics is particularly important for isolated cases, in which Xlinked and de novo autosomal dominant variants are not uncommon. In addition, new geneor mutation-specific therapies are emerging, underlining the importance of identifying causative mutations in each individual. Sanger sequencing of selected genes followed by costeffective targeted next-generation sequencing (NGS) can identify defects in known IRDassociated genes in the majority of the cases. Exome NGS in combination with genetic linkage or homozygosity mapping studies can aid the identification of the remaining causal genes. As these are thought to be mutated in ,1% of the cases, validation through functional modeling in, for example, zebrafish and/or replication through the genotyping of large patient cohorts is required. In the near future, whole genome NGS in combination with transcriptome NGS may reveal mutations that are currently hidden in the noncoding regions of the human genome.

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Segregation of a mutation in CNGB1 encoding the β-subunit of the rod cGMP-gated channel in a family with autosomal recessive retinitis pigmentosa

Cited by 109 publications

References 27 publications

Impaired Channel Targeting and Retinal Degeneration in Mice Lacking the Cyclic Nucleotide-Gated Channel Subunit CNGB1

Impaired Channel Targeting and Retinal Degeneration in Mice Lacking the Cyclic Nucleotide-Gated Channel Subunit CNGB1

Knockout of GARPs and the β-subunit of the rod cGMP-gated channel disrupts disk morphogenesis and rod outer segment structural integrity

Genomic Approaches For the Discovery of Genes Mutated in Inherited Retinal Degeneration

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