The Experts below are selected from a list of 1026 Experts worldwide ranked by ideXlab platform
Keiko Miyadera - One of the best experts on this subject based on the ideXlab platform.
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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.
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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
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Canine genome assembly correction facilitates identification of a MAP9 deletion as a potential age of onset modifier for RPGRIP1-associated canine retinal degeneration
Mammalian Genome, 2016Co-Authors: Oliver P Forman, Keiko Miyadera, Rebekkah J. Hitti, Mike Boursnell, David Sargan, Cathryn MellershAbstract:Retinal degeneration (RD) in the Miniature Long Haired Dachshund (MLHD) is a cone-rod dystrophy resulting in eventual blindness in affected individuals. In a previous study, a 44-nucleotide insertion (ins44) in exon 2 of RPGRIP1 was associated with RD. However, results on an extended population of MLHD revealed a variable RD onset age for ins44 homozygous dogs. Further investigations using a genome-wide association study comparing early onset and late onset RD cases identified an age of onset modifying locus for RD, approximately 30 Mb upstream of RPGRIP1 on chr15. In this investigation, target enriched sequencing identified a MAP9 deletion spanning approximately 22 kb associated with early RD onset. Identification of the deletion required correction to the CanFam3.1 genome build as canine MAP9 is part of a historic tandem duplication, resulting in incomplete assembly of this genome region. The deletion breakpoints were identified in MAP9 intron 10 and in a downstream partial MAP9 pseudogene. The fusion of these two genes, which we have called MAP9 _ EORD (microtubule-associated protein, early onset retinal degeneration), is in frame and is expressed at the RNA level, with the 3′ region containing several predicted deleterious variants. We speculate that MAP9 associates with α-tubulin in the basal body of the cilium. RPGRIP1 is also known to locate to the cilium, where it is closely associated with RPGR. RPGRIP1 mutations also cause redistribution of α-tubulin away from the ciliary region in photoreceptors. Hence, a MAP9 partial deficit is a particularly attractive candidate to synergise with a partial RPGRIP1 deficit to cause a more serious disease.
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© 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
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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.
Gustavo D Aguirre - One of the best experts on this subject based on the ideXlab platform.
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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.
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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.
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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.
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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.
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analysis of six candidate genes as potential modifiers of disease expression in canine xlpra1 a model for human x linked retinitis pigmentosa 3
Molecular Vision, 2007Co-Authors: Richard Guyon, Gregory M Acland, Susan E Pearcekelling, Caroline J Zeiss, Gustavo D AguirreAbstract:Purpose: Canine X-linked progressive retinal atrophy (XLPRA) is caused by mutations in RPGR exon ORF15, which is also a mutation hotspot in human X-linked retinitis pigmentosa 3 (RP3). The XLPRA1 form of disease has shown extensive phenotypic variability in a colony of dogs that all inherited the same mutant X-chromosome. This variability in onset and severity makes XLPRA1 a valuable model to use to identify genes influencing photoreceptors degeneration in dog and to elucidate molecular mechanisms underlying RP in its human homolog. In this study, RPGRIP1, RANBP2, NPM1, PDE6D, NPHP5, and ABCA4 genes were selected on the basis of interaction with RPGR or RPGRIP1 or their implication in related retinal diseases, and were investigated as candidate genetic modifiers of XLPRA1. Methods: A pedigree derived from an affected male dog outcrossed to unrelated normal mix bred or purebred females was used. Morphologic examination revealed phenotypic variability in the affected dogs characterized as mild, moderate, or severe. Single nucleotide polymorphisms (SNPs) and indel-containing markers spanning the entire genes were designed, based on the canine sequence and the Broad Institute SNP library, and genotyped on the pedigree. For each candidate gene, haplotypes were identified and their frequencies in severely and moderately affected dogs were compared to detect a putative correlation between a gene-specific haplotype(s), and severity level of the disease. Primers were derived from expressed sequence tags (ESTs) and predicted transcripts to assess the relative retinal expression of the six genes of interest in normal and affected retinas of different ages. Results: Four to seven haplotypes per gene were identified. None of the haplotypes of RPGRIP1, NPM1, PDE6D, NPHP5, RANBP2, and ABCA4 were found to co-segregate with the moderate or severe phenotype. No significant difference in the retinal expression levels of the candidate genes was observed between normal and affected dogs. Conclusions: The haplotype distribution of RPGRIP1, NPM1, PDE6D, NPHP5, RANBP2, and ABCA4 suggests these genes are not modifiers of the disease phenotype observed in the XLPRA1 pedigree. The RPGRORF15 stop mutation does not affect the retinal expression of these genes at the mRNA level in the pre-degenerate stage of disease, but no conclusions can be made at this time about changes that may occur at the protein level.
Monkol Lek - One of the best experts on this subject based on the ideXlab platform.
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contribution of noncoding pathogenic variants to RPGRIP1 mediated inherited retinal degeneration
Genetics in Medicine, 2019Co-Authors: Farzad Jamshidi, Emily Place, Sudeep Mehrotra, Daniel Navarrogomez, Mathew Maher, Kari Branham, Elise Valkanas, Timothy J Cherry, Monkol LekAbstract:With the advent of gene therapies for inherited retinal degenerations (IRDs), genetic diagnostics will have an increasing role in clinical decision-making. Yet the genetic cause of disease cannot be identified using exon-based sequencing for a significant portion of patients. We hypothesized that noncoding pathogenic variants contribute significantly to the genetic causality of IRDs and evaluated patients with single coding pathogenic variants in RPGRIP1 to test this hypothesis. IRD families underwent targeted panel sequencing. Unsolved cases were explored by exome and genome sequencing looking for additional pathogenic variants. Candidate pathogenic variants were then validated by Sanger sequencing, quantitative polymerase chain reaction, and in vitro splicing assays in two cell lines analyzed through amplicon sequencing. Among 1722 families, 3 had biallelic loss-of-function pathogenic variants in RPGRIP1 while 7 had a single disruptive coding pathogenic variants. Exome and genome sequencing revealed potential noncoding pathogenic variants in these 7 families. In 6, the noncoding pathogenic variants were shown to lead to loss of function in vitro. Noncoding pathogenic variants were identified in 6 of 7 families with single coding pathogenic variants in RPGRIP1. The results suggest that noncoding pathogenic variants contribute significantly to the genetic causality of IRDs and RPGRIP1-mediated IRDs are more common than previously thought.
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contribution of non coding mutations to RPGRIP1 mediated inherited retinal degeneration
bioRxiv, 2018Co-Authors: Farzad Jamshidi, Emily Place, Sudeep Mehrotra, Daniel Navarrogomez, Mathew Maher, Elise Valkanas, Timothy J Cherry, Monkol Lek, Daniel G Macarthur, Eric A PierceAbstract:Purpose: With the advent of gene therapies for inherited retinal degenerations (IRDs), genetic diagnostics will have an increasing role in clinical decision making. Yet a significant portion of IRDs remains unsolved. We hypothesized that noncoding mutation solve a significant portion of such cases. Focusing on RPGRIP1, we examined the significance of noncoding mutations. Methods: A cohort of IRD families underwent targeted panel sequencing. Unsolved cases were explored by whole exome and whole genome sequencing to look for copy number and intronic mutations. The candidates were then validated by Sanger sequencing, quantitative PCR, and in vitro splicing assays in two cell lines analyzed through amplicon sequencing. Results: Among 1722 families, three had biallelic loss of function mutations in RPGRIP1 and were considered solved while seven had a single disruptive coding mutation. Whole exome and whole genome sequencing revealed noncoding candidates in these seven families. In six, the noncoding mutations were shown to lead to loss of function in vitro. Additionally, an unannotated exon of RPGRIP1 was discovered and the efficacy of amplicon sequencing in assessing splicing mutations highlighted. Conclusion: RPGRIP1 mediated IRDs are more common than previously thought. Addition of copy number and 30 base pair flanking intronic sequences will increase the sensitivity of diagnostic panels.
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contribution of structural and intronic mutations to RPGRIP1 mediated inherited retinal dystrophies
bioRxiv, 2017Co-Authors: Farzad Jamshidi, Emily Place, Daniel Navarrogomez, Mathew Maher, Elise Valkanas, Monkol Lek, Daniel G Macarthur, Kinga M Bujakowska, Eric A PierceAbstract:With the completion of the first phase 3 human gene therapy randomized clinical trial, in the form of voretigene neparvovec for RPE65-mediated inherited retinal dystrophy, as well as the advent of more than 20 other gene therapy trials for inherited retinal disorders, accurate genetic diagnostics will have an increasingly important role in clinical decision-making. Current genetic diagnostic testing panels primarily focus on coding sequences. However, we find that structural and intronic variations are crucial in solving ambiguous cases. We present four families in whom more in depth sequencing and bioinformatic analyses led to the identification of non-coding and structural variations in RPGRIP1 as the cause of disease. In the process we describe ten novel RPGRIP1 mutations. We suggest an expansion of both sequencing and bioinformatics tools in the diagnostics of inherited retinal degenerations to increase sensitivity and to make confident calls before enrolling patients in specific gene therapy clinical trials.
Dan Doherty - One of the best experts on this subject based on the ideXlab platform.
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super resolution microscopy reveals that disruption of ciliary transition zone architecture is a cause of joubert syndrome
bioRxiv, 2017Co-Authors: Xiaoyu Shi, Dan Doherty, Bo Huang, Galo Garcia, Julie C Van De Weghe, Ryan Mcgorty, Gregory J Pazour, Jeremy F ReiterAbstract:Diverse human ciliopathies, including nephronophthisis (NPHP), Meckel syndrome (MKS) and Joubert syndrome (JBTS), can be caused by mutations affecting components of the transition zone, a ciliary domain near its base. The transition zone controls the protein composition of the ciliary membrane, but how it does so is unclear. To better understand the transition zone and its connection to ciliopathies, we defined the arrangement of key proteins in the transition zone using two-color stochastic optical reconstruction microscopy (STORM). This mapping revealed that NPHP and MKS complex components form nested rings comprised of nine-fold doublets. The NPHP complex component RPGRIP1L forms a smaller diameter transition zone ring within the MKS complex rings. JBTS-associated mutations in RPGRIP1L disrupt the architecture of the MKS and NPHP rings, revealing that vertebrate RPGRIP1L has a key role in organizing transition zone architecture. JBTS-associated mutations in TCTN2, encoding an MKS complex component, also displace proteins of the MKS and NPHP complexes from the transition zone, revealing that RPGRIP1L and TCTN2 have interdependent roles in organizing transition zone architecture. To understand how altered transition zone architecture affects developmental signaling, we examined the localization of the Hedgehog pathway component SMO in human fibroblasts derived from JBTS-affected individuals. We found that diverse ciliary proteins, including SMO, accumulate at the transition zone in wild type cells, suggesting that the transition zone is a way station for proteins entering and exiting the cilium. JBTS-associated mutations in RPGRIP1L disrupt SMO accumulation at the transition zone and the ciliary localization of SMO. We propose that the disruption of transition zone architecture in JBTS leads to a failure of SMO to accumulate at the transition zone, disrupting developmental signaling in JBTS.
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hypomorphism for RPGRIP1l a ciliary gene vicinal to the fto locus causes increased adiposity in mice
Cell Metabolism, 2014Co-Authors: George Stratigopoulos, Jayne Martin F Carli, Diana R Oday, Liheng Wang, Charles A Leduc, Patricia Lanzano, Wendy K Chung, Michael Rosenbaum, Dieter Egli, Dan DohertyAbstract:Common polymorphisms in the first intron of FTO are associated with increased body weight in adults. Previous studies have suggested that a CUX1-regulatory element within the implicated FTO region controls expression of FTO and the nearby ciliary gene, RPGRIP1L. Given the role of ciliary genes in energy homeostasis, we hypothesized that mice hypomorphic for RPGRIP1l would display increased adiposity. We find that RPGRIP1l⁺/⁻ mice are hyperphagic and fatter, and display diminished suppression of food intake in response to leptin administration. In the hypothalamus of RPGRIP1l⁺/⁻ mice, and in human fibroblasts with hypomorphic mutations in RPGRIP1L, the number of AcIII-positive cilia is diminished, accompanied by impaired convening of the leptin receptor to the vicinity of the cilium, and diminished pStat3 in response to leptin. These findings suggest that RPGRIP1L may be partly or exclusively responsible for the obesity susceptibility signal at the FTO locus.
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mutations in 3 genes mks3 cc2d2a and RPGRIP1l cause coach syndrome joubert syndrome with congenital hepatic fibrosis
Journal of Medical Genetics, 2010Co-Authors: Dan Doherty, Melissa A Parisi, Meral Gunayaygun, M Almateen, Daniel Bates, Carol L Clericuzio, H Demir, Michael O Dorschner, Laura S Finn, A J Van EssenAbstract:Objective To identify genetic causes of COACH syndrome Background COACH syndrome is a rare autosomal recessive disorder characterised by Cerebellar vermis hypoplasia, Oligophrenia (developmental delay/mental retardation), Ataxia, Coloboma, and Hepatic fibrosis. The vermis hypoplasia falls in a spectrum of mid-hindbrain malformation called the molar tooth sign (MTS), making COACH a Joubert syndrome related disorder (JSRD). Methods In a cohort of 251 families with JSRD, 26 subjects in 23 families met criteria for COACH syndrome, defined as JSRD plus clinically apparent liver disease. Diagnostic criteria for JSRD were clinical findings (intellectual impairment, hypotonia, ataxia) plus supportive brain imaging findings (MTS or cerebellar vermis hypoplasia). MKS3/TMEM67 was sequenced in all subjects for whom DNA was available. In COACH subjects without MKS3 mutations, CC2D2A, RPGRIP1L and CEP290 were also sequenced. Results 19/23 families (83%) with COACH syndrome carried MKS3 mutations, compared to 2/209 (1%) with JSRD but no liver disease. Two other families with COACH carried CC2D2A mutations, one family carried RPGRIP1L mutations, and one lacked mutations in MKS3, CC2D2A, RPGRIP1L and CEP290. Liver biopsies from three subjects, each with mutations in one of the three genes, revealed changes within the congenital hepatic fibrosis/ductal plate malformation spectrum. In JSRD with and without liver disease, MKS3 mutations account for 21/232 families (9%). Conclusions Mutations in MKS3 are responsible for the majority of COACH syndrome, with minor contributions from CC2D2A and RPGRIP1L; therefore, MKS3 should be the first gene tested in patients with JSRD plus liver disease and/or coloboma, followed by CC2D2A and RPGRIP1L.
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mutations in the gene encoding the basal body protein RPGRIP1l a nephrocystin 4 interactor cause joubert syndrome
Nature Genetics, 2007Co-Authors: Heleen H Arts, Dan Doherty, Melissa A Parisi, Sylvia E C Van Beersum, Stef J F Letteboer, Nicholas T Gorden, Theo A Peters, Tina Marker, Krysta Voesenek, Aileen KartonoAbstract:Protein-protein interaction analyses have uncovered a ciliary and basal body protein network that, when disrupted, can result in nephronophthisis (NPHP), Leber congenital amaurosis, Senior-Loken syndrome (SLSN) or Joubert syndrome (JBTS). However, details of the molecular mechanisms underlying these disorders remain poorly understood. RPGRIP1-like protein (RPGRIP1L) is a homolog of RPGRIP1 (RPGR-interacting protein 1), a ciliary protein defective in Leber congenital amaurosis. We show that RPGRIP1L interacts with nephrocystin-4 and that mutations in the gene encoding nephrocystin-4 (NPHP4) that are known to cause SLSN disrupt this interaction. RPGRIP1L is ubiquitously expressed, and its protein product localizes to basal bodies. Therefore, we analyzed RPGRIP1L as a candidate gene for JBTS and identified loss-of-function mutations in three families with typical JBTS, including the characteristic mid-hindbrain malformation. This work identifies RPGRIP1L as a gene responsible for JBTS and establishes a central role for cilia and basal bodies in the pathophysiology of this disorder.
Khaled Bouhouche - One of the best experts on this subject based on the ideXlab platform.
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MKS-NPHP module proteins control ciliary shedding at the transition zone
PLoS biology, 2020Co-Authors: Delphine Gogendeau, Sylvie Schneider-maunoury, Michel Lemullois, Pierrick Le Borgne, Manon Castelli, Anne Aubusson-fleury, Olivier Arnaiz, Jean Cohen, Christine Vesque, Khaled BouhoucheAbstract:Ciliary shedding occurs from unicellular organisms to metazoans. Although required during the cell cycle and during neurogenesis, the process remains poorly understood. In all cellular models, this phenomenon occurs distal to the transition zone (TZ), suggesting conserved molecular mechanisms. The TZ module proteins (Meckel Gruber syndrome [MKS]/Nephronophtysis [NPHP]/Centrosomal protein of 290 kDa [CEP290]/Retinitis pigmentosa GTPase regulator-Interacting Protein 1-Like Protein [RPGRIP1L]) are known to cooperate to establish TZ formation and function. To determine whether they control deciliation, we studied the function of 5 of them (Transmembrane protein 107 [TMEM107], Transmembrane protein 216 [TMEM216], CEP290, RPGRIP1L, and NPHP4) in Paramecium. All proteins are recruited to the TZ of growing cilia and localize with 9-fold symmetry at the level of the most distal part of the TZ. We demonstrate that depletion of the MKS2/TMEM216 and TMEM107 proteins induces constant deciliation of some cilia, while depletion of either NPHP4, CEP290, or RPGRIP1L prevents Ca2+/EtOH deciliation. Our results constitute the first evidence for a role of conserved TZ proteins in deciliation and open new directions for understanding motile cilia physiology.
