The Experts below are selected from a list of 2874 Experts worldwide ranked by ideXlab platform
Gustavo D Aguirre - One of the best experts on this subject based on the ideXlab platform.
-
variabilities in retinal function and structure in a canine model of Cone Rod Dystrophy associated with rpgrip1 support multigenic etiology
Scientific Reports, 2017Co-Authors: Felipe Pompeo Marinho, Gustavo D Aguirre, Simone Iwabe, Kendra Mcdaid, Evelyn Santana, Keiko MiyaderaAbstract:Defects in the cilia gene RPGRIP1 cause Leber congenital amaurosis and Cone-Rod Dystrophy in humans. A form of canine Cone-Rod Dystrophy (cord1) was originally associated with a homozygous insertion in RPGRIP1 (RPGRIP1 ins/ins) as the primary disease locus while a homozygous deletion in MAP9 (MAP9 del/del) was later identified as a modifier associated with the early onset form. However, we find further variability in Cone electroretinograms (ERGs) ranging from normal to absent in an extended RPGRIP1 ins/ins canine colony, irrespective of the MAP9 genotype. Ophthalmoscopically, Cone ERGabsent RPGRIP1 ins/ins eyes show discolouration of the tapetal fundus with varying onset and disease progression, while sd-OCT reveals atrophic changes. Despite marked changes in Cone ERG and retinal morphology, photopic vision-guided behaviour is comparable between normal and Cone ERGabsent RPGRIP1 ins/ins littermates. Cone morphology of the dogs lacking Cone ERG are truncated with shortened outer and inner segments. Immunohistochemically, Cone ERGabsent RPGRIP1 ins/ins retinas have extensive L/M-opsin mislocalization, lack CNGB3 labelling in the L/M-Cones, and lack GC1 in all Cones. Our results indicate that cord1 is a multigenic disease in which mutations in neither RPGRIP1 nor MAP9 alone lead to visual deficits, and additional gene(s) contribute to Cone-specific functional and morphologic defects.
-
exclusion of rpgrip1 ins44 from primary causal association with early onset Cone Rod Dystrophy in dogs
Investigative Ophthalmology & Visual Science, 2012Co-Authors: Tatyana N Kuznetsova, Simone Iwabe, Kathleen Boeszebattaglia, Sue Pearcekelling, Yim Changmin, Kendra Mcdaid, Keiko Miyadera, Andras M Komaromy, Gustavo D AguirreAbstract:Purpose. Canine Cone–Rod Dystrophy 1 (cord1) has been previously mapped to CFA15, and a homozygous 44-bp insertion in exon 2 (Ins44) of canine RPGRIP1 (cRPGRIP1Ins/Ins) has been associated with the disease. However, from the recent identification of a significant discordance in genotype–phenotype association, we have reexamined the role of cRPGRIP1 in cord1.
-
rpgrip1 and Cone Rod Dystrophy in dogs
Advances in Experimental Medicine and Biology, 2012Co-Authors: Tatyana N Kuznetsova, Barbara Zangerl, Gustavo D AguirreAbstract:Cone–Rod dystrophies (crd) represent a group of progressive inherited blinding diseases characterized by primary dysfunction and loss of Cone photoreceptors accompanying or preceding Rod death. Recessive crd type 1 was described in dogs associated with an RPGRIP1 exon 2 mutation, but with lack of complete concordance between genotype and phenotype. This review highlights role of the RPGRIP1, a component of complex protein networks, and its function in the primary cilium, and discusses the potential mechanisms of genotype–phenotype discordance observed in dogs with the RPGRIP1 mutation.
-
structural organization and expression pattern of the canine rpgrip1 isoforms in retinal tissue
Investigative Ophthalmology & Visual Science, 2011Co-Authors: Tatyana N Kuznetsova, Barbara Zangerl, Orly Goldstein, Gregory M Acland, Gustavo D AguirreAbstract:The RPGRIP1 gene encodes retinitis pigmentosa GTPase interacting protein 1, and mutations in the human gene are associated with Leber congenital amaurosis (LCA),1–3 juvenile retinitis pigmentosa,4 a late-onset Cone–Rod Dystrophy,5 and Cone–Rod Dystrophy type 1 in dogs.6,7 Human RPGRIP1 consists of 25 exons, of which 24 code for a 1259-amino-acid protein.1,3 Exons 6 to 13, 14 to 16, and 18 to 24 encode, respectively, the α-helical coil–coiled protein interaction motif of members of the structural maintenance of chromosomes (SMC) superfamily, two protein kinase C conserved region 2 motifs (C2), and conserved RPGR-interacting domain (RID).8–10 The biological functions of RPGRIP1 are complex. In the eye, it is expressed in amacrine neurons8,11 and photoreceptors,9,12 and in numerous other tissues, albeit at greatly reduced levels.9,12 Moreover, the existence of multiple isoforms, with species-specific subcellular localization patterns (e.g., connecting cilium,11,13 photoreceptor inner14 and outer8,11 segments, and basal bodies of cells with primary cilia15), suggests that different isoforms perform cell-specific functions. RPGRIP1 is required not only for disc morphogenesis of the outer segments (OS),16 but also for the formation of the OS itself, particularly in Rods.17 A general role of RPGRIP1 as a scaffold protein has been suggested,13 and it interacts directly or indirectly with RPGR,9,16,18 NPHP4,10 and RanBP2.8 It has been shown that RPGRIP1 can be proteolytically processed, rendering its N-terminal domain competent for nuclear localization,19 suggesting that it may be involved in regulating gene expression. Although a mutation in RPGRIP1 is causally associated with canine Cone–Rod Dystrophy,6,7 a potential large-animal model for gene-based therapies,20 little is known about the canine gene structure, organization, and expression, and the molecular basis of the disease. To assess the structure/function relationship of the RPGRIP1 isoforms, we characterized the full-length transcript of canine RPGRIP1 (cRPGRIP1) and its several alternatively spliced isoforms and evaluated the 5′- and 3′-UTRs of RPGRIP1 transcripts. Our results identified a novel complex 5′ and 3′ splicing pattern and further described the complete structure of six cRPGRIP1 alternatively spliced variants driven by two different promoters.
-
an adam9 mutation in canine Cone Rod Dystrophy 3 establishes homology with human Cone Rod Dystrophy 9
Molecular Vision, 2010Co-Authors: Orly Goldstein, Jason G Mezey, Adam R Boyko, Chuan Gao, Wei Wang, Carlos Bustamante, Lynne J Anguish, J Jordan, Susan E Pearcekelling, Gustavo D AguirreAbstract:Purpose To identify the causative mutation in a canine Cone-Rod Dystrophy (crd3) that segregates as an adult onset disorder in the Glen of Imaal Terrier breed of dog.
Alexander M Dizhoor - One of the best experts on this subject based on the ideXlab platform.
-
gucy2d mutations in retinal guanylyl cyclase 1 provide biochemical reasons for dominant Cone Rod Dystrophy but not for stationary night blindness
Journal of Biological Chemistry, 2020Co-Authors: Igor V Peshenko, Elena V Olshevskaya, Alexander M DizhoorAbstract:Mutations in the GUCY2D gene coding for the dimeric human retinal membrane guanylyl cyclase (RetGC) isozyme RetGC1 cause various forms of blindness, ranging from Rod dysfunction to Rod and Cone degeneration. We tested how the mutations causing recessive congenital stationary night blindness (CSNB), recessive Leber's congenital amaurosis (LCA1), and dominant Cone–Rod Dystrophy-6 (CORD6) affected RetGC1 activity and regulation by RetGC-activating proteins (GCAPs) and retinal degeneration-3 protein (RD3). CSNB mutations R666W, R761W, and L911F, as well as LCA1 mutations R768W and G982VfsX39, disabled RetGC1 activation by human GCAP1, -2, and -3. The R666W and R761W substitutions compromised binding of GCAP1 with RetGC1 in HEK293 cells. In contrast, G982VfsX39 and L911F RetGC1 retained the ability to bind GCAP1 in cyto but failed to effectively bind RD3. R768W RetGC1 did not bind either GCAP1 or RD3. The co-expression of GUCY2D allelic combinations linked to CSNB did not restore RetGC1 activity in vitro. The CORD6 mutation R838S in the RetGC1 dimerization domain strongly dominated the Ca2+ sensitivity of cyclase regulation by GCAP1 in RetGC1 heteRodimer pRoduced by co-expression of WT and the R838S subunits. It required higher Ca2+ concentrations to decelerate GCAP-activated RetGC1 heteRodimer—6-fold higher than WT and 2-fold higher than the Ser838-harboring homodimer. The heteRodimer was also more resistant than homodimers to inhibition by RD3. The observed biochemical changes can explain the dominant CORD6 blindness and recessive LCA1 blindness, both of which affect Rods and Cones, but they cannot explain the selective loss of Rod function in recessive CSNB.
-
gucy2d Cone Rod Dystrophy 6 is a phototransduction disease triggered by abnormal calcium feedback on retinal membrane guanylyl cyclase 1
The Journal of Neuroscience, 2018Co-Authors: Shinya Sato, Elena V Olshevskaya, Igor V Peshenko, Vladimir J Kefalov, Alexander M DizhoorAbstract:The Arg838Ser mutation in retinal membrane guanylyl cyclase 1 (RetGC1) has been linked to autosomal dominant Cone-Rod Dystrophy type 6 (CORD6). It is believed that photoreceptor degeneration is caused by the altered sensitivity of RetGC1 to calcium regulation via guanylyl cyclase activating proteins (GCAP). To determine the mechanism by which this mutation leads to degeneration, we investigated the structure and function of Rod photoreceptors in two transgenic mouse lines, 362 and 379, expressing R838S RetGC1. In both lines, Rod outer segments became shorter than in their non-transgenic siblings by 3-4 weeks of age, before the eventual photoreceptor degeneration. Despite the shortening of their outer segments, the dark current of transgenic Rods was 1.5—2.2-fold higher than in non-transgenic controls. Similarly, the dim flash response amplitude in R838S + Rods was larger, time to peak was delayed, and flash sensitivity was increased, all suggesting elevated dark-adapted free cGMP in transgenic Rods. In Rods expressing R838S RetGC1, dark current noise increased and the exchange current, detected after a saturating flash, became more pronounced. These results suggest disrupted Ca 2+ phototransduction feedback and abnormally high free Ca 2+ concentration in the outer segments. Notably, photoreceptor degeneration, which typically occurred after 3 months of age in R838S RetGC1 transgenic mice in GCAP1,2 +/+ or GCAP1,2 +/- backgrounds, was completely prevented in GCAP1,2 -/- mice lacking Ca 2+ feedback to guanylyl cyclase. In summary, the dysregulation of guanylyl cyclase in RetGC1-linked CORD6 is a ‘phototransduction disease9, associated with increase in free cGMP and Ca 2+ levels in photoreceptors. SIGNIFICANCE STATEMENT In a mouse model expressing human membrane guanylyl cyclase 1 (RetGC1, GUCY2D ), a mutation associated with early progressing congenital blindness, Cone-Rod Dystrophy type 6 (CORD6), deregulates calcium-sensitive feedback of phototransduction to the cyclase mediated by calcium-sensor proteins GCAPs. The abnormal calcium sensitivity of the cyclase increases cGMP-gated dark current in the Rod outer segments, re-shapes Rod photoresponses, and triggers photoreceptor death. This work is the first to demonstrate a direct physiological effect of GUCY2D CORD6-linked mutation on photoreceptor physiology in vivo . It also identifies the abnormal regulation of the cyclase by calcium-sensor proteins as the main trigger for the photoreceptor death.
-
gucy2d Cone Rod Dystrophy 6 is a phototransduction disease triggered by abnormal calcium feedback on retinal membrane guanylyl cyclase 1
The Journal of Neuroscience, 2018Co-Authors: Shinya Sato, Elena V Olshevskaya, Igor V Peshenko, Vladimir J Kefalov, Alexander M DizhoorAbstract:The Arg838Ser mutation in retinal membrane guanylyl cyclase 1 (RetGC1) has been linked to autosomal dominant Cone-Rod Dystrophy type 6 (CORD6). It is believed that photoreceptor degeneration is caused by the altered sensitivity of RetGC1 to calcium regulation via guanylyl cyclase activating proteins (GCAPs). To determine the mechanism by which this mutation leads to degeneration, we investigated the structure and function of Rod photoreceptors in two transgenic mouse lines, 362 and 379, expressing R838S RetGC1. In both lines, Rod outer segments became shorter than in their nontransgenic siblings by 3-4 weeks of age, before the eventual photoreceptor degeneration. Despite the shortening of their outer segments, the dark current of transgenic Rods was 1.5-2.2-fold higher than in nontransgenic controls. Similarly, the dim flash response amplitude in R838S+ Rods was larger, time to peak was delayed, and flash sensitivity was increased, all suggesting elevated dark-adapted free cGMP in transgenic Rods. In Rods expressing R838S RetGC1, dark-current noise increased and the exchange current, detected after a saturating flash, became more pronounced. These results suggest disrupted Ca2+ phototransduction feedback and abnormally high free-Ca2+ concentration in the outer segments. Notably, photoreceptor degeneration, which typically occurred after 3 months of age in R838S RetGC1 transgenic mice in GCAP1,2+/+ or GCAP1,2+/- backgrounds, was prevented in GCAP1,2-/- mice lacking Ca2+ feedback to guanylyl cyclase. In summary, the dysregulation of guanylyl cyclase in RetGC1-linked CORD6 is a "phototransduction disease," which means it is associated with increased free-cGMP and Ca2+ levels in photoreceptors.SIGNIFICANCE STATEMENT In a mouse model expressing human membrane guanylyl cyclase 1 (RetGC1, GUCY2D), a mutation associated with early progressing congenital blindness, Cone-Rod Dystrophy type 6 (CORD6), deregulates calcium-sensitive feedback of phototransduction to the cyclase mediated by guanylyl cyclase activating proteins (GCAPs), which are calcium-sensor proteins. The abnormal calcium sensitivity of the cyclase increases cGMP-gated dark current in the Rod outer segments, reshapes Rod photoresponses, and triggers photoreceptor death. This work is the first to demonstrate a direct physiological effect of GUCY2D CORD6-linked mutation on photoreceptor physiology in vivo It also identifies the abnormal regulation of the cyclase by calcium-sensor proteins as the main trigger for the photoreceptor death.
Keiko Miyadera - One of the best experts on this subject based on the ideXlab platform.
-
variabilities in retinal function and structure in a canine model of Cone Rod Dystrophy associated with rpgrip1 support multigenic etiology
Scientific Reports, 2017Co-Authors: Felipe Pompeo Marinho, Gustavo D Aguirre, Simone Iwabe, Kendra Mcdaid, Evelyn Santana, Keiko MiyaderaAbstract:Defects in the cilia gene RPGRIP1 cause Leber congenital amaurosis and Cone-Rod Dystrophy in humans. A form of canine Cone-Rod Dystrophy (cord1) was originally associated with a homozygous insertion in RPGRIP1 (RPGRIP1 ins/ins) as the primary disease locus while a homozygous deletion in MAP9 (MAP9 del/del) was later identified as a modifier associated with the early onset form. However, we find further variability in Cone electroretinograms (ERGs) ranging from normal to absent in an extended RPGRIP1 ins/ins canine colony, irrespective of the MAP9 genotype. Ophthalmoscopically, Cone ERGabsent RPGRIP1 ins/ins eyes show discolouration of the tapetal fundus with varying onset and disease progression, while sd-OCT reveals atrophic changes. Despite marked changes in Cone ERG and retinal morphology, photopic vision-guided behaviour is comparable between normal and Cone ERGabsent RPGRIP1 ins/ins littermates. Cone morphology of the dogs lacking Cone ERG are truncated with shortened outer and inner segments. Immunohistochemically, Cone ERGabsent RPGRIP1 ins/ins retinas have extensive L/M-opsin mislocalization, lack CNGB3 labelling in the L/M-Cones, and lack GC1 in all Cones. Our results indicate that cord1 is a multigenic disease in which mutations in neither RPGRIP1 nor MAP9 alone lead to visual deficits, and additional gene(s) contribute to Cone-specific functional and morphologic defects.
-
Multiple Mechanisms Contribute to Leakiness of a Frameshift Mutation in Canine Cone-Rod Dystrophy
2016Co-Authors: Keiko Miyadera, Cathryn S Mellersh, Ian Brierley, David R. SarganAbstract:Mutations in RPGRIP1 are associated with early onset retinal degenerations in humans and dogs. Dogs homozygous for a 44 bp insertion including a polyA29 tract potentially leading to premature truncation of the protein, show Cone Rod degeneration. This is rapid and blinding in a colony of dogs in which the mutation was characterised but in dogs with the same mutation in the pet population there is very variable disease severity and rate of progression. Objective: We hypothesized that this variability must be associated with leakiness of the RPGRIP1 mutation, allowing continued RPGRIP1 pRoduction. The study was designed to discover mechanisms that might allow such leakiness. Methods: We analysed alternate start sites and splicing of RPGRIP1 transcripts; variability of polyAn length in the insertion and slippage at polyAn during transcription/translation. Results and Significance: We observed a low rate of use of alternative start codons having potential to allow forms of transcript not including the insertion, with the possibility of encoding truncated functional RPGRIP1 protein isoforms. Complex alternative splicing was observed, but did not increase this potential. Variable polyAn length was confirmed in DNA from different RPGRIP12/2 dogs, yet polyAn variability did not correspond with the clinical phenotypes and no individual was found that carried a polyAn tract capable of encoding an in-frame variant. Remarkably though, in luciferase reporter gene assays, out-of-frame inserts still allowed downstream reporter gene expression at some 40 % of the efficiency of in
-
© 2009 Molecular Vision Phenotypic variation and genotype-phenotype discordance in canine Cone-Rod Dystrophy with an RPGRIP1 mutation
2013Co-Authors: Keiko Miyadera, Claudia Busse, Kumiko Kato, Tsuyoshi Tokuriki, Kyohei Morimoto, Hiroyuki Ogawa, Jesús Aguirre-hernández, Keith Barnett, Nigel Holmes, Nobuo SasakiAbstract:Purpose: Previously, a 44 bp insertion in exon 2 of retinitis pigmentosa GTPase interacting protein 1 (RPGRIP1) was identified as the cause of Cone-Rod Dystrophy 1 (cord1), a recessive form of progressive retinal atrophy (PRA) in the Miniature Longhaired Dachshund (MLHD), a dog model for Leber congenital amaurosis. The cord1 locus was mapped using MLHDs from an inbred colony with a homogeneous early onset disease phenotype. In this paper, the MLHD pet population was studied to investigate phenotypic variation and genotype-phenotype correlation. Further, the cord1 locus was fine-mapped using PRA cases from the MLHD pet population to narrow the critical region. Other dog breeds were also screened for the RGPRIP1 insertion. Methods: This study examined phenotypic variation in an MLHD pet population that included 59 sporadic PRA cases and 18 members of an extended family with shared environment and having six PRA cases. Ophthalmologic evaluations included behavioral abnormalities, responses to menace and light, fundoscopy, and electroretinography (ERG). The RPGRIP1 insertion was screened for in all cases and 200 apparently normal control MLHDs and in 510 dogs from 66 other breed. To fine-map the cord1 locus in the MLHD, 74 PRA cases and 86 controls aged 4 years or more were genotyped for 24 polymorphic markers within the previously mapped cord1 critical region of 14.15 Mb
-
exclusion of rpgrip1 ins44 from primary causal association with early onset Cone Rod Dystrophy in dogs
Investigative Ophthalmology & Visual Science, 2012Co-Authors: Tatyana N Kuznetsova, Simone Iwabe, Kathleen Boeszebattaglia, Sue Pearcekelling, Yim Changmin, Kendra Mcdaid, Keiko Miyadera, Andras M Komaromy, Gustavo D AguirreAbstract:Purpose. Canine Cone–Rod Dystrophy 1 (cord1) has been previously mapped to CFA15, and a homozygous 44-bp insertion in exon 2 (Ins44) of canine RPGRIP1 (cRPGRIP1Ins/Ins) has been associated with the disease. However, from the recent identification of a significant discordance in genotype–phenotype association, we have reexamined the role of cRPGRIP1 in cord1.
-
genome wide association study in rpgrip1 dogs identifies a modifier locus that determines the onset of retinal degeneration
Mammalian Genome, 2012Co-Authors: Cathryn S Mellersh, M E G Boursnell, Keiko Miyadera, Kumiko Kato, David R. SarganAbstract:Cone-Rod Dystrophy (CRD) is a form of inherited retinal degeneration (RD) causing blindness in man as well as in several breeds of dog. Previously, a 44 bp insertion in RPGRIP1 (retinitis pigmentosa GTPase regulator interacting protein-1) was associated with a recessive early-onset CRD (Cone-Rod Dystrophy 1, cord1) in a Miniature longhaired dachshund (MLHD) research colony. Yet in the MLHD pet population, extensive range of the onset age has been observed among RD cases, with some RPGRIP1 −/− dogs lacking obvious clinical signs. Phenotypic variation has been known in human homologous diseases, including retinitis pigmentosa and Leber congenital amaurosis, indicating possible involvement of modifiers. To explore additional genetic loci associated with the phenotypic variation observed in MLHDs, a genome-wide association study was carried out using Canine SNP20 arrays in 83 RPGRIP1 −/− MLHDs with variable ages of onset or no clinical abnormality. Using these samples, comparison of 31 early-onset RD cases against 49 controls (15 late-onset RD and 34 normal dogs combined) identified a strong association (P = 5.05 × 10−13) at a single locus on canine chromosome 15. At this locus, the majority of early-onset RD cases but few of the controls were homozygous for a 1.49 Mb interval containing ~11 genes. We conclude that homozygosity at both RPGRIP1 and the newly mapped second locus is necessary to develop early-onset RD, whereas RPGRIP1 −/− alone leads to late-onset RD or no apparent clinical phenotype. This study establishes a unique model of canine RD requiring homozygous mutations at two distinct genetic loci for the manifestation of early-onset RD.
Alan C. Bird - One of the best experts on this subject based on the ideXlab platform.
-
pathological and electrophysiological features of a canine Cone Rod Dystrophy in the miniature longhaired dachshund
Investigative Ophthalmology & Visual Science, 2007Co-Authors: Clare Turney, Alan C. Bird, Keith C Barnett, N Victor H Chong, Robert Alexander, Chris Hogg, Lorraine Fleming, Deborah J Flack, Graham E. HolderAbstract:PURPOSE. To characterize the electrophysiological and histopathological features of a retinal degenerative disease in a colony of miniature longhaired dachshunds known to have a form of progressive retinal atrophy (PRA). METHODS. Serial electroretinograms were recorded from affected homozygous (n = 36) and heterozygous (n = 15) dogs. Morphologic investigations including immunohistochemistry and lectin histochemistry were performed on selected homozygous animals (n = 15). RESULTS. Clinical findings included loss of tapetal hyperreflectivity. The mode of inheritance was autosomal recessive. An early dramatic reduction of Cone-specific ERG amplitude with a more modest reduction in Rod b-wave amplitude was demonstrated. Progressively, Rod specific responses diminished until there were no recordable responses to the ERG stimuli at 40 weeks of age. Morphologic changes confirmed early Cone inner and outer segment loss. Other abnormalities included opsin mislocalization and outer nuclear layer thinning due to the subsequent loss of Rod photoreceptors. CONCLUSIONS. A novel canine Cone-Rod Dystrophy has been identified.
-
mutations in the retinal guanylate cyclase retgc 1 gene in dominant Cone Rod Dystrophy
Human Molecular Genetics, 1998Co-Authors: Rosemary E Kelsell, Annette M. Payne, Alan C. Bird, Isabelle Perrault, Josseline Kaplan, Anthony T Moore, Kevin Gregoryevans, Rueybing Yang, David L Garbers, David M HuntAbstract:The dominant Cone‐Rod Dystrophy gene CORD6 has previously been mapped to within an 8 cM interval on chromosome 17p12‐p13. The retinal-specific guanylate cyclase gene (RETGC-1), which maps to within this genetic interval and previously was implicated in Leber’s congenital amaurosis, was screened for mutations within this family and in a panel of small families and individuals with various Cone and Cone‐ Rod Dystrophy phenotypes. A missense mutation (E837D) was identified in affected members of the CORD6 family, as well as a second missense mutation (R838C) in three other families with dominant Cone‐Rod Dystrophy. RETGC-1 is only the fourth gene to be implicated in Cone‐Rod Dystrophy and this is the first report of dominant mutations in this gene.
-
localization of a gene cord7 for a dominant Cone Rod Dystrophy to chromosome 6q
American Journal of Human Genetics, 1998Co-Authors: Rosemary E Kelsell, Graham E. Holder, Alan C. Bird, Anthony T Moore, Kevin Gregoryevans, Cheryl Y Gregoryevans, M Jay, Bernhard H F Weber, David M HuntAbstract:We thank the family members for their cooperation in this study. This work was supported by the Wellcome Trust (grant 041905), the Frost Charitable Trust, and the Foundation Fighting Blindness.
-
A Mutation in Guanylate Cyclase Activator 1A (GUCA1A) in an Autosomal Dominant Cone Dystrophy Pedigree Mapping to a New Locus on Chromosome 6p21.1
Human Molecular Genetics, 1998Co-Authors: Annette M. Payne, Susan M. Downes, Graham E. Holder, Martin J. Warren, Alan C. Bird, David A.r. Bessant, Rachel Taylor, Shomi S. BhattacharyaAbstract:We report a mutation (Y99C) in guanylate cyclase activator 1A (GUCA1A), the gene for guanylate cyclase activating protein (GCAP1), in a family with autosomal dominant Cone Dystrophy. Linkage analysis excluded all the known Cone and Cone-Rod Dystrophy loci, except the chromosome 6p21.1 region. This is known to contain the RDS gene, which is associated with dominant Cone-Rod Dystrophy. Screening of the RDS gene by heteRoduplex analysis and direct sequencing failed to demonstrate sequence changes in the coding region of this gene. The gene for GCAP1, a calcium binding protein which is highly expressed in photoreceptor outer segments, is also located in 6p21.1. It was screened for mutations, and all affected individuals showed a single base pair missense mutation (A-->G) at codon 99 in exon 2 of this gene generating a tyrosine-to-cysteine change in the GCAP1 protein. This change was absent from 206 unrelated normal controls. We propose that this change would at least disrupt the EF3handof GCAP1 thereby preventing calcium binding and consequently interfere with activation. The resulting effect on cGMP pRoduction would predictably modify the number of open cGMP gated cation channels, and could explain the ultimate demise of Cone photoreceptor cells.
David M Hunt - One of the best experts on this subject based on the ideXlab platform.
-
mutations in the retinal guanylate cyclase retgc 1 gene in dominant Cone Rod Dystrophy
Human Molecular Genetics, 1998Co-Authors: Rosemary E Kelsell, Annette M. Payne, Alan C. Bird, Isabelle Perrault, Josseline Kaplan, Anthony T Moore, Kevin Gregoryevans, Rueybing Yang, David L Garbers, David M HuntAbstract:The dominant Cone‐Rod Dystrophy gene CORD6 has previously been mapped to within an 8 cM interval on chromosome 17p12‐p13. The retinal-specific guanylate cyclase gene (RETGC-1), which maps to within this genetic interval and previously was implicated in Leber’s congenital amaurosis, was screened for mutations within this family and in a panel of small families and individuals with various Cone and Cone‐ Rod Dystrophy phenotypes. A missense mutation (E837D) was identified in affected members of the CORD6 family, as well as a second missense mutation (R838C) in three other families with dominant Cone‐Rod Dystrophy. RETGC-1 is only the fourth gene to be implicated in Cone‐Rod Dystrophy and this is the first report of dominant mutations in this gene.
-
localization of a gene cord7 for a dominant Cone Rod Dystrophy to chromosome 6q
American Journal of Human Genetics, 1998Co-Authors: Rosemary E Kelsell, Graham E. Holder, Alan C. Bird, Anthony T Moore, Kevin Gregoryevans, Cheryl Y Gregoryevans, M Jay, Bernhard H F Weber, David M HuntAbstract:We thank the family members for their cooperation in this study. This work was supported by the Wellcome Trust (grant 041905), the Frost Charitable Trust, and the Foundation Fighting Blindness.
-
genetic linkage of Cone Rod retinal Dystrophy to chromosome 19q and evidence for segregation distortion
Nature Genetics, 1994Co-Authors: K Evans, Cheryl Y Gregory, Alan Fryer, Josephine Duvallyoung, Chris F Inglehearn, Joanne L Whittaker, Rachel Butler, Neil D Ebenezer, David M Hunt, S S BhattacharyaAbstract:Inherited retinal dystrophies are the most common cause of childhood blindness in the developed world. Cone-Rod retinal dystrophies are severe examples of this group of disorders. Analysis of a large Cone-Rod Dystrophy pedigree suggested that inheritance within the family was influenced by meiotic drive (p = 0.008), a rare segregation distortion in human genetics. Two-point linkage analysis showed significant linkage with three markers mapping to chromosome 19q. Multipoint analysis gave a maximum lod score of 10.08 (theta = 0.05) distal to D19S47. Cone-Rod Dystrophy is therefore assigned to 19q13.1-q13.2 and a new candidate locus for other retinal dystrophies is identified.