X linked cone-rod dystrophy, CORDX3, is caused by a mutation in the CACNA1F gene

Jalkanen, Reetta; Mäntyjärvi, Maija; Tobias, Rose; Isosomppi, Juha; Em, Sankila; Alitalo, Tiina; Nt, Bech-Hansen

doi:10.1136/jmg.2006.040741

Cited by 84 publications

(68 citation statements)

References 45 publications

(53 reference statements)

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“…It is not clear if these functional abnormalities noted in the α 1F -KO mutant are stable across age. Nevertheless, these functional abnormalities appear to distinguish α 1F -KO mice from patients with CSNB2 and raise the possibility that the α 1F -KO mouse develops cone photoreceptor dysfunction or degeneration, a possibility discussed by Mansergh et al (2005) and consistent with recent reports linking some Cacna1f mutations with progressive retinal disorders (Nakamura et al, 2003;Jalkanen et al, 2004;Hope et al, 2005).…”

Section: Ganglion Cell Response Properties In Nob2 Micesupporting

confidence: 76%

Thenob2mouse, a null mutation inCacna1f: Anatomical and functional abnormalities in the outer retina and their consequences on ganglion cell visual responses

et al. 2006

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Glutamate release from photoreceptor terminals is controlled by voltage-dependent calcium channels (VDCCs). In humans, mutations in the Cacna1f gene, encoding the α 1F subunit of VDCCs, underlie the incomplete form of X-linked congenital stationary night blindness (CSNB2). These mutations impair synaptic transmission from rod and cone photoreceptors to bipolar cells. Here, we report anatomical and functional characterizations of the retina in the nob2 (no b-wave 2) mouse, a naturally occurring mutant caused by a null mutation in Cacna1f. Not surprisingly, the b-waves of both the light-and dark-adapted electroretinogram are abnormal in nob2 mice. The outer plexiform layer (OPL) is disorganized, with extension of ectopic neurites through the outer nuclear layer that originate from rod bipolar and horizontal cells, but not from hyperpolarizing bipolar cells. These ectopic neurites continue to express mGluR6, which is frequently associated with profiles that label with the

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Section: Ganglion Cell Response Properties In Nob2 Micesupporting

confidence: 76%

Thenob2mouse, a null mutation inCacna1f: Anatomical and functional abnormalities in the outer retina and their consequences on ganglion cell visual responses

et al. 2006

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“…A total of 41 of the validated candidate genes have human orthologs, 7 of which have previously been associated with vision disorders. cac, which encodes a calcium channel, has seven human orthologs that also encode calcium channel subunits, of which CACNA1F has been associated with congenital night blindness (CSNB2A) (78), Aland Island eye disease (AIED) (79,80), and X-linked conerod dystrophy (CORDX3) (81). fz encodes a seven-transmembrane helix containing protein necessary for binding Wnt ligands in the noncanonical Wnt signaling pathway (82) and has 10 human orthologs encoding frizzled class receptors, of which FZD4 is associated with exudative vitreoretinopathy (83).…”

Section: Discussionmentioning

confidence: 99%

Genetic architecture of natural variation in visual senescence in Drosophila

Carbone

Yamamoto

Huang

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Senescence, i.e., functional decline with age, is a major determinant of health span in a rapidly aging population, but the genetic basis of interindividual variation in senescence remains largely unknown. Visual decline and age-related eye disorders are common manifestations of senescence, but disentangling age-dependent visual decline in human populations is challenging due to inability to control genetic background and variation in histories of environmental exposures. We assessed the genetic basis of natural variation in visual senescence by measuring age-dependent decline in phototaxis using Drosophila melanogaster as a genetic model system. We quantified phototaxis at 1, 2, and 4 wk of age in the sequenced, inbred lines of the Drosophila melanogaster Genetic Reference Panel (DGRP) and found an average decline in phototaxis with age. We observed significant genetic variation for phototaxis at each age and significant genetic variation in senescence of phototaxis that is only partly correlated with phototaxis. Genome-wide association analyses in the DGRP and a DGRP-derived outbred, advanced intercross population identified candidate genes and genetic networks associated with eye and nervous system development and function, including seven genes with human orthologs previously associated with eye diseases. Ninety percent of candidate genes were functionally validated with targeted RNAi-mediated suppression of gene expression. Absence of candidate genes previously implicated with longevity indicates physiological systems may undergo senescence independent of organismal life span. Furthermore, we show that genes that shape early developmental processes also contribute to senescence, demonstrating that senescence is part of a genetic continuum that acts throughout the life span.aging | behavioral genetics | DGRP GWA analysis | phototaxis | xQTL mapping

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“…59 The gene encoding the L-type calcium channel ␣ 1 -subunit, CACNA1F, is associated with other types of retinal dysfunction-namely, incomplete X-linked congenital stationary night blindness (CSNB2) 60,61 and X-linked cone-rod dystrophy (CORDX3). 62 The main cellular function of Ca v 1.4 (␣ 1F ) is thought to be the mediation of neurotransmitter release from photoreceptor and bipolar cells, 63 a function that could be assumed for Ca v 1.3 (␣ 1D ) as well. Therefore, and because of the Ca v 1.3 (␣ 1D ) expression in the developing retina, CACNA1D is a candidate gene for retinal dysfunction in humans.…”

Section: Cacna1d In Diseasementioning

confidence: 99%

Association of Whirlin with Ca_v1.3 (α_1D) Channels in Photoreceptors, Defining a Novel Member of the Usher Protein Network

Kersten

Wijk

Reeuwijk

et al. 2010

Invest. Ophthalmol. Vis. Sci.

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PURPOSE.Usher syndrome is the most common form of hereditary deaf-blindness. It is both clinically and genetically heterogeneous. The USH2D protein whirlin interacts via its PDZ domains with other Usher-associated proteins containing a C-terminal type I PDZ-binding motif. These proteins co-localize with whirlin at the region of the connecting cilium and at the synapse of photoreceptor cells. This study was undertaken to identify novel, Usher syndrome-associated, interacting partners of whirlin and thereby obtain more insights into the function of whirlin. METHODS.The database of ciliary proteins was searched for proteins that are present in both the retina and inner ear and contain a PDZ-binding motif. Interactions with whirlin were evaluated by yeast two-hybrid analyses and validated by glutathione S-transferase pull-down assays, co-immunoprecipitation, and co-localization in the retina with immunofluorescence and immunoelectron microscopy. RESULTS.The L-type calcium channel subunit Ca v 1.3 (␣ 1D ) specifically interacts with whirlin. In adult photoreceptors, Ca v 1.3 (␣ 1D ) and whirlin co-localize in the region of the connecting cilium and at the synapse. During murine embryonic development, the expression patterns of the Whrn and Cacna1d genes show significant overlap and include expression in the eye, the inner ear, and the central nervous system. CONCLUSIONS. The findings indicate that Ca v 1.3 (␣ 1D ) is connected to the Usher protein network. This conclusion leads to the hypothesis that, in the retina, whirlin scaffolds Ca v 1.3 (␣ 1D ) and therefore contributes to the organization of calcium channels in the photoreceptor cells, where both proteins may be involved in membrane fusions. (Invest Ophthalmol Vis Sci.

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X linked cone-rod dystrophy, CORDX3, is caused by a mutation in the CACNA1F gene

Cited by 84 publications

References 45 publications

Thenob2mouse, a null mutation inCacna1f: Anatomical and functional abnormalities in the outer retina and their consequences on ganglion cell visual responses

Thenob2mouse, a null mutation inCacna1f: Anatomical and functional abnormalities in the outer retina and their consequences on ganglion cell visual responses

Genetic architecture of natural variation in visual senescence in Drosophila

Association of Whirlin with Ca_v1.3 (α_1D) Channels in Photoreceptors, Defining a Novel Member of the Usher Protein Network

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X linked cone-rod dystrophy, CORDX3, is caused by a mutation in the CACNA1F gene

Cited by 84 publications

References 45 publications

Thenob2mouse, a null mutation inCacna1f: Anatomical and functional abnormalities in the outer retina and their consequences on ganglion cell visual responses

Thenob2mouse, a null mutation inCacna1f: Anatomical and functional abnormalities in the outer retina and their consequences on ganglion cell visual responses

Genetic architecture of natural variation in visual senescence in Drosophila

Association of Whirlin with Cav1.3 (α1D) Channels in Photoreceptors, Defining a Novel Member of the Usher Protein Network

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Association of Whirlin with Ca_v1.3 (α_1D) Channels in Photoreceptors, Defining a Novel Member of the Usher Protein Network