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- Mutations in AGBL5, Encoding α-Tubulin Deglutamylase, Are Associated With Autosomal Recessive Retinitis Pigmentosa
Galuh D. N. Astuti, Gavin Arno, Sarah Hull, Laurence Pierrache, Hanka Venselaar, Keren Carss, F. Lucy Raymond, Rob W. J. Collin, Sultana M. H. Faradz, L. Ingeborgh van den Born, Andrew R. Webster, Frans P. M. Cremers | Investigative Ophthalmology & Visual Science | Nov 2016 | Vol.57 | 6180-6187 | doi.org/10.1167/iovs.16-20148 Abstract Purpose AGBL5 , encoding ATP/GTP binding protein-like 5, was previously proposed as an autosomal recessive retinitis pigmentosa (arRP) candidate gene based on the identification of missense variants in two families. In this study, we performed next-generation sequencing to reveal additional RP cases with AGBL5 variants, including protein-truncating variants. Methods Whole-genome sequencing (WGS) or whole-exome sequencing (WES) was performed in three probands. Subsequent Sanger sequencing and segregation analysis were performed in the selected candidate genes. The medical history of individuals carrying AGBL5 variants was reviewed and additional ophthalmic examinations were performed, including fundus photography, fundus autofluorescence imaging, and optical coherence tomography. Results AGBL5 variants were identified in three unrelated arRP families, comprising homozygous variants in family 1 (c.1775G>A:p.(Trp592*)) and family 2 (complex allele: c.[323C>G; 2659T>C]; p.[(Pro108Arg; 887Argext 1)]), and compound heterozygous variants (c.752T>G:p.(Val251Gly) and c.1504dupG:p.(Ala502Glyfs*15)) in family 3. All affected individuals displayed typical RP phenotypes. Conclusions Our study convincingly shows that variants in AGBL5 are associated with arRP. The identification of AGBL5 and TTLL5 , a previously described RP-associated gene encoding the tubulin tyrosine ligase-like family, member 5 protein, highlights the importance of poly- and deglutamylation in retinal homeostasis. Further studies are required to investigate the underlying disease mechanism associated with AGBL5 variants. Read more, click here
- Mutations in AGBL5 associated with Retinitis pigmentosa
Diego I. Paredes, Nicholas R. Bello, Jenina E. Capasso, Rebecca Procopio, Alex V. Levin | Ophthalmic Genetics | 45(3) | 275-280 | December 11, 2023 | doi.org/10.1080/13816810.2023.2291687 Background Retinitis pigmentosa (RP) is the leading cause of heritable retinal visual impairment. Clinically, it is characterized by a variable onset of progressive night blindness and visual field constriction. RP is characterized by wide genetic heterogeneity with a broad range of potential genes involved in the genesis of this disease. Very few cases have been reported of RP due to pathogenic variants in AGBL5 . Materials and Methods We report two patients with RP and bilallelic pathogenic variants in AGBL5. Results Genetic sequencing showed one homozygous AGBL5 missense variant in one patient and a homozygous nonsense variant in the other. These patients presented with progressive peripheral vision loss and nyctalopia. Their RP phenotypes were similar to previous reports in literature. Conclusion These two cases provide further evidence regarding the relationship of pathogenic variants in AGBL5 as a cause of autosomal recessive RP. Read more, click here
- CLINICAL TRIAL | Natural History of PRPF31 Mutation-Associated Retinal Dystrophy
A study on Retinitis Pigmentosa and Retinal Dystrophy Description Summary The purpose of this study is to characterize the natural history through temporal systemic evaluation of subjects identified with PRPF31 mutation-associated retinal dystrophy , also called retinitis pigmentosa type 11, or RP11. Assessments will be completed to measure and evaluate structural and functional visual changes including those impacting patient quality of life associated with this inherited retinal condition and observing how these changes evolve over time. Official Title A Natural History and Outcome Measure Discovery Study of PRPF31 Mutation-Associated Retinal Dystrophy Details This is a multi-center, longitudinal, prospective observational natural history study of participants with a molecularly confirmed mutation in PRPF31. Approximately 50 participants (100 eyes) at approximately 5 sites will be enrolled into a uniform protocol for follow-up and evaluations. Each participant's medical record will be reviewed for historical information, and clinical data will be recorded in a secure database. Natural history data will be collected prospectively and will include ophthalmic exams, imaging studies, electrophysiological testing, functional mobility evaluations, and questionnaires. Assessments will be conducted in a standardized protocol every 16 weeks ± 4 weeks for the first year and then every 24 weeks ± 4 weeks for up to approximately 4 years after each participant's baseline visit (Visit 2). Keywords Retinitis Pigmentosa , Eye Diseases, Hereditary, Retinal Dystrophies, Retinal Dystrophy Rod, Retinal Dystrophy Rod Progressive , Retinitis Pigmentosa Type 11, RP11, PRPF31, Retinal Dystrophy, PRPF31 Mutation-Associated Retinal Dystrophy, Eye Diseases, Retinitis, Hereditary Eye Diseases, Inborn Genetic Diseases Click here to learn more and indicate interest
- Dissecting the role of EYS in retinal degeneration: clinical and molecular aspects and its implications for future therapy
Ana B. Garcia-Delgado , Lourdes Valdes-Sanchez , Maria Jose Morillo-Sanchez , Beatriz Ponte-Zuñiga , Francisco J. Diaz-Corrales , Berta de la Cerda | Orphanet Journal of Rare Diseases | 16, 222 | 17 May 2021 | https://doi.org/10.1186/s13023-021-01843-z Abstract Mutations in the EYS gene are one of the major causes of autosomal recessive retinitis pigmentosa. EYS-retinopathy presents a severe clinical phenotype, and patients currently have no therapeutic options. The progress in personalised medicine and gene and cell therapies hold promise for treating this degenerative disease. However, lack of understanding and incomplete comprehension of disease's mechanism and the role of EYS in the healthy retina are critical limitations for the translation of current technical advances into real therapeutic possibilities. This review recapitulates the present knowledge about EYS-retinopathies, their clinical presentations and proposed genotype–phenotype correlations. Molecular details of the gene and the protein, mainly based on animal model data, are analysed. The proposed cellular localisation and roles of this large multi-domain protein are detailed. Future therapeutic approaches for EYS-retinopathies are discussed. Background Retinitis pigmentosa (RP, OMIM #26800) is the most common form of inherited retinal degeneration (IRD), with an estimated prevalence of 1 per 4,000 people. Although RP is a rare disease, it represents the primary cause of hereditary blindness in adults, affecting more than one million people worldwide [ 1 ]. EYS is a major causative gene for autosomal recessive RP (arRP) [ 2 ] in all ethnicities. EYS-retinopathy manifests early in life and produces a severe disability, currently without therapeutic options. The study of the disease's molecular mechanism has been hampered by the lack of a representative animal model for this human IRD. Information on the cellular localisation and molecular features of EYS, obtained from different vertebrate animal models, is summarised in this review to get insight into this protein's possible roles in the human retina. Gene therapy is emerging as a safe and effective treatment for some types of RP caused by specific genes such as RPE65 . Future therapeutic approaches for EYS-retinopathies are discussed based on this large gene's limitations and the current advanced therapies state-of-the-art. Click here to read entire article References Menghini M, Cehajic-Kapetanovic J, MacLaren RE. Monitoring progression of retinitis pigmentosa: current recommendations and recent advances. Expert Opin Orphan Drugs. 2020;8(2–3):67–78. Abd El-Aziz MM, Barragan I, O’Driscoll CA, Goodstadt L, Prigmore E, Borrego S, et al. EYS, encoding an ortholog of Drosophila spacemaker, is mutated in autosomal recessive retinitis pigmentosa. Nat Genet. 2008;40(11):1285–7.
- ARL2BP, a protein linked to retinitis pigmentosa, is needed for normal photoreceptor cilia doublets and outer segment structure
Abigail R Moye , Ratnesh Singh , Victoria A Kimler , Tanya L Dilan , Daniella Munezero , Thamaraiselvi Saravanan , Andrew F X Goldberg , Visvanathan Ramamurthy | Molecular Biology of the Cell | 2018 Jul 1 | Vol 29(13) | pages 1590–1598 | doi: 10.1091/mbc.E18-01-0040 Abstract The outer segment (OS) of photoreceptor cells is an elaboration of a primary cilium with organized stacks of membranous disks that contain the proteins needed for phototransduction and vision. Though ciliary formation and function has been well characterized, little is known about the role of cilia in the development of photoreceptor OS. Nevertheless, progress has been made by studying mutations in ciliary proteins, which often result in malformed OSs and lead to blinding diseases. To investigate how ciliary proteins contribute to OS formation, we generated a knockout (KO) mouse model for ARL2BP, a ciliary protein linked to retinitis pigmentosa. The KO mice display an early and progressive reduction in visual response. Before photoreceptor degeneration, we observed disorganization of the photoreceptor OS, with vertically aligned disks and shortened axonemes. Interestingly, ciliary doublet microtubule (MT) structure was also impaired, displaying open B-tubule doublets, paired with loss of singlet MTs. On the basis of results from this study, we conclude that ARL2BP is necessary for photoreceptor ciliary doublet formation and axoneme elongation, which is required for OS morphogenesis and vision. Introduction Photoreceptors are ciliated neurons that absorb photons and convert light into electrical signals. These neurons are compartmentalized with outer and inner segments (OS and IS) bridged by a narrow connecting cilium (CC, corresponds to the ciliary transition zone) with an extended axoneme ( Pearring et al. , 2013 ; Goldberg et al. , 2016 ; May-Simera et al. , 2017 ). The OS contains stacked membranous disks that anchor proteins that participate in phototransduction ( Molday and Moritz, 2015 ). Remarkably, photoreceptors shed 10% of their disks every day ( Young, 1967 ; Goldberg et al. , 2016 ). To maintain the OSs, photoreceptors need to ensure continuous transport of proteins and membranes from their site of synthesis in the IS through the CC to the OS ( Young, 1967 ). In addition to facilitating protein movement, the photoreceptor axoneme is thought to play a structural role in the formation and continual replacement of OS disks ( Liu et al. , 2004 ). Though the photoreceptor cilium is highly modified in function, the basic structure is consistent with immotile primary cilia seen in other tissues, containing 9 + 0 MT morphology that undergoes a switch from doublet microtubules (DMTs) to singlet MTs approximately one-third of the way up the axoneme ( Brown et al. , 1963 ; Steinberg and Wood, 1975 ; Knabe and Kuhn, 1997 ; Insinna et al. , 2008 ; Wensel et al. , 2016 ). The axonemal DMTs consist of an A-tubule containing 13 tubulin protofilaments joined to a B-tubule containing 10 tubulin protofilaments, with an 11th nontubulin complex linking the inner junction of A and B tubules (see Figure 7A later in this article) ( Linck and Stephens, 2007 ; Nicastro et al. , 2011 ; Pigino et al. , 2012 ; Linck et al. , 2014 ; Ichikawa et al. , 2017 ). Defects in the structural integrity of photoreceptor CC/axoneme lead to retinal degenerative diseases such as retinitis pigmentosa (RP), Lebers congenital amaurosis, and multiple ciliopathies ( Pierce et al. , 1999 ; Ramamurthy and Cayouette, 2009 ; Omori et al. , 2010 ; Boldt et al. , 2011 ; Bujakowska et al. , 2017 ). For example, mice lacking retinitis pigmentosa 1 (RP1), a protein that links the OS disks to the axoneme, displayed shortened axonemes and disordered OS disk structure ( Liu et al. , 2003 , 2004). Conversely, the absence of male germ-cell associated kinase (MAK) in murine retina resulted in extended axonemes, as well as disorganized OS disks ( Omori et al. , 2010 ). Despite the importance of the ciliary axoneme in photoreceptor structure and function, relatively little is known of the mechanism and players behind ciliogenesis and disk organization in the OS. Click here to read entire article References Anand M, Khanna H. (2012). 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- Retinitis pigmentosa associated with a mutation in BEST1
Lauren A Dalvin , Jackson E Abou Chehade , John Chiang , Josefine Fuchs , Raymond Iezzi , Alan D Marmorstein | American Journal Ophthalmology Case Reports | 2016 Mar 30 | Vol 2 | pages 11–17 | doi: 10.1016/j.ajoc.2016.03.005 Purpose There is only one prior report associating mutations in BEST1 with a diagnosis of retinitis pigmentosa (RP). The imaging studies presented in that report were more atypical of RP and shared features of autosomal recessive bestrophinopathy and autosomal dominant vitreoretinochoroidopathy. Here, we present a patient with a clinical phenotype consistent with classic features of RP. Observations The patient in this report was diagnosed with simplex RP based on clinically-evident bone spicules with characteristic ERG and EOG findings. The patient had associated massive cystoid macular edema which resolved following a short course of oral acetazolamide. Genetic testing revealed that the patient carries a novel heterozygous deletion mutation in BEST1 which is not carried by either parent. While this suggests BEST1 is causative, the patient also inherited heterozygous copies of several mutations in other genes known to cause recessive retinal degenerative disease. Conclusions and Importance How some mutations in BEST1 associate with peripheral retinal degeneration phenotypes, while others manifest as macular degeneration phenotypes is currently unknown. We speculate that RP due to BEST1 mutation requires mutations in other modifier genes. 1. Introduction Mutations in the gene BEST1 (MIM 607854 ), which encodes the protein Bestrophin-1 (Best1), are responsible for 5 clinically distinct inherited retinopathies: Best vitelliform macular dystrophy (BVMD), adult-onset vitelliform macular dystrophy (AVMD), autosomal recessive bestrophinopathy (ARB), autosomal dominant vitreoretinochoroidopathy (ADVIRC), and retinitis pigmentosa (RP) [1] , [2] , [3] , [4] , [5] , [6] , [7] . While mutations in BEST1 are widely accepted to cause BVMD, AVMD, ARB, and ADVIRC, there has been only one prior report of mutations in BEST1 causing RP [7] . The clinical images in that paper shared phenotypic features of ARB and ADVIRC, causing some to question whether the subjects in the study have classic RP, and thus, whether BEST1 can cause RP [8] . BEST1 encodes bestrophin 1 (Best1) a homo-oligomeric anion channel that, within the eye, is exclusively expressed in retinal pigment epithelial (RPE) cells, where it normally localizes to the basolateral plasma membrane and plays a critical role in regulating Ca2+ signaling [9] , [10] , [11] . BEST1 mutations are typically thought to be disease-causing when they result in loss of anion-channel activity [12] , [13] . Previous studies have shown that the first ∼174 amino acids of Best1 are sufficient to permit oligomerization and that the first ∼366 amino acids are sufficient for both homo-oligomerization and channel activity [14] , [15] . It has also been demonstrated that mislocalization alone is not pathogenic [14] . Here, we present a patient with RP due to a deletion mutation in BEST1, H422fsX431. Click here to read the entire article. References Marquardt A., Stohr H., Passmore L.A., Kramer F., Rivera A., Weber B.H. Mutations in a novel gene, VMD2, encoding a protein of unknown properties cause juvenile-onset vitelliform macular dystrophy (Best's disease) Hum. Mol. Genet. 1998;7:1517–1525. doi: 10.1093/hmg/7.9.1517. [ DOI ] [ PubMed ] [ Google Scholar ] Marmorstein A.D., Cross H.E., Peachey N.S. Functional roles of bestrophins in ocular epithelia. Prog. Retin Eye Res. 2009;28:206–226. doi: 10.1016/j.preteyeres.2009.04.004. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] Petrukhin K., Koisti M.J., Bakall B. Identification of the gene responsible for best macular dystrophy. Nat. Genet. 1998;19:241–247. doi: 10.1038/915. [ DOI ] [ PubMed ] [ Google Scholar ] Kramer F., White K., Pauleikhoff D. Mutations in the VMD2 gene are associated with juvenile-onset vitelliform macular dystrophy (Best disease) and adult vitelliform macular dystrophy but not age-related macular degeneration. Eur. J. Hum. Genet. 2000;8:286–292. doi: 10.1038/sj.ejhg.5200447. 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[ Google Scholar ] Marmorstein A.D., Marmorstein L.Y., Rayborn M., Wang X., Hollyfield J.G., Petrukhin K. Bestrophin, the product of the best vitelliform macular dystrophy gene (VMD2), localizes to the basolateral plasma membrane of the retinal pigment epithelium. Proc. Natl. Acad. Sci. U. S. A. 2000;97:12758–12763. doi: 10.1073/pnas.220402097. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] Marmorstein L.Y., Wu J., McLaughlin P. The light peak of the electroretinogram is dependent on voltage-gated calcium channels and antagonized by bestrophin (best-1) J. Gen. Physiol. 2006;127:577–589. doi: 10.1085/jgp.200509473. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] Zhang Y., Stanton J.B., Wu J. Suppression of Ca2+ signaling in a mouse model of best disease. Hum. Mol. Genet. 2010;19:1108–1118. doi: 10.1093/hmg/ddp583. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] Hartzell H.C., Qu Z., Yu K., Xiao Q., Chien L.T. Molecular physiology of bestrophins: multifunctional membrane proteins linked to best disease and other retinopathies. Physiol. Rev. 2008;88:639–672. doi: 10.1152/physrev.00022.2007. [ DOI ] [ PubMed ] [ Google Scholar ] Xiao Q., Hartzell H.C., Yu K. Bestrophins and retinopathies. Pflugers Arch. 2010;460:559–569. doi: 10.1007/s00424-010-0821-5. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] Johnson A.A., Lee Y.S., Chadburn A.J. Disease-causing mutations associated with four bestrophinopathies exhibit disparate effects on the localization, but not the oligomerization, of Bestrophin-1. Exp. Eye Res. 2014;121:74–85. doi: 10.1016/j.exer.2014.02.006. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ]
- Functional analysis of BBS3 A89V that results in non-syndromic retinal degeneration
Pamela R Pretorius , Mohammed A Aldahmesh , Fowzan S Alkuraya , Val C Sheffield , Diane C Slusarski | Human Molecular Genetics | 2011 Jan 31 | 20(8) | 1625–1632 | doi: 10.1093/hmg/ddr039 Abstract Bardet–Biedl syndrome (BBS) is a syndromic form of retinal degeneration. Recently, homozygosity mapping with a consanguineous family with isolated retinitis pigmentosa identified a missense mutation in BBS3, a known BBS gene. The mutation in BBS3 encodes a single amino acid change at position 89 from alanine to valine. Since this amino acid is conserved in a wide range of vertebrates, we utilized the zebrafish model system to functionally characterize the BBS3 A89V mutation. Knockdown of bbs3 in zebrafish alters intracellular transport, a phenotype observed with knockdown of all BBS genes in the zebrafish, as well as visual impairment. Here, we find that BBS3 A89V is sufficient to rescue the transport delays induced by the loss of bbs3, indicating that this mutation does not affect the function of BBS3 as it relates to syndromic disease. BBS3L A89V, however, was unable to rescue vision impairment, highlighting a role for a specific amino acid within BBS3 that is necessary for visual function, but dispensable in other cell types. These data aid in our understanding of why patients with the BBS3 A89V missense mutation only present with isolated retinitis pigmentosa. Introduction Bardet–Biedl syndrome (BBS, OMIM 209900) is a genetically heterogeneous autosomal recessive disorder characterized by retinitis pigmentosa, obesity, polydactyly, renal abnormalities, hypogenitalism and cognitive impairment ( 1 – 4 ). Moreover, BBS is associated with an increased risk for hypertension, diabetes and heart defects ( 1 , 2 , 5 ). BBS patients present with early and progressive photoreceptor degeneration and are blind by the third decade of life ( 2 , 6 – 13 ). To date, 12 BBS ( BBS1–12 ) genes are reported to individually cause BBS ( 14 – 27 ). Additionally, hypomorphic mutations in MKS1 and CEP290 have been associated with BBS, representing BBS13 and BBS14 , respectively ( 28 ). The BBS genes belong to multiple protein families and function cannot be defined based on homology; however, recent advances in molecular pathophysiology and animal models have helped to elucidate why 14 different genes can lead to the same phenotype. Work in mouse, zebrafish, Caenorhabditis elegans and Chlamydomonas has provided multiple lines of evidence supporting a role for BBS proteins in cilia function and intraflagellar and/or intracellular transport ( 19 , 22 , 23 , 26 , 29 – 36 ). Although progress has been made in understanding the pathophysiology of BBS, there are major gaps in our understanding of the precise cellular function of the BBS proteins. BBS3 (ARL6, ADP-ribosylation factor-like), a member of the Ras family of small GTP-binding proteins, was initially identified as a BBS gene through computational genomics and high-density single nucleotide polymorphism (SNP) genotyping ( 21 , 22 ). Several mutations (G2X, T31M, T31R, P108L, R122X, G169A and L170W) leading to BBS have been reported throughout BBS3 ( 21 , 22 , 37 ). Knockdown of bbs3 using an antisense oligonucleotide [Morpholino (MO)] results in two cardinal features of BBS in the zebrafish: reduced size of the ciliated Kupffer's Vesicle and delays in intracellular melanosome transport ( 35 , 38 ). These prototypical phenotypes are preset with knockdown of all BBS genes in the zebrafish ( 26 , 34 , 35 , 38 ). Recently, we identified a second longer eye-specific transcript of BBS3 , BBS3L , which is required for retinal organization and function in both the mouse and zebrafish ( 38 ). Knockdown of either both bbs3 transcripts or bbs3L alone leads to vision impairment in zebrafish. To determine the functional requirement of each transcript, RNA encoding either human BBS3 or BBS3L was co-injected with the bbs3 aug MO, which targets both transcripts. We determined that human BBS3 RNA is sufficient to suppress the melanosome transport delays, but not the vision defect. In contrast, BBS3L RNA was sufficient to rescue the vision defect; however, it was unable to suppress the cardinal phenotypes of BBS seen in the zebrafish, supporting a retina specific role for BBS3L ( 38 ). BBS is rare in the general population; however, the study of this disease can offer insight into normal retinal development as well as provide an understanding of the pathophysiology involved in non-syndromic forms of BBS. Homozygosity mapping of a consanguineous Saudi Arabian family has identified a missense mutation (A89V) in BBS3 that leads to non-syndromic retinitis pigmentosa ( 39 , 40 ). The identification of specific mutations in the same gene that results in either syndromic or non-syndromic retinitis pigmentosa will provide insight into tissue-specific functional regions of BBS3 in the retina. Moreover, understanding the functional domains of proteins involved in vision aids in our understanding of not only the disease state, but also normal vision development. Here we report the functional characterization of the BBS3 missense mutation (A89V), which occurs in a highly conserved region of BBS3. The function of the BBS3 A89V mutation was evaluated by utilizing gene knockdown of bbs3 coupled with RNA rescue in the zebrafish. We examined the intracellular transport of melanosomes, a cardinal feature of BBS gene knockdown in the zebrafish, and visual function using a vision startle assay. The A89V mutation can suppress the melanosome transport defects, but not the vision impairment observed with the loss of bbs3 . Thus, the missense mutation identified in patients with non-syndromic retinal degeneration has uncovered an amino acid in BBS3 that is necessary for vision. The A89V mutation is able to function in melanosome transport, demonstrating that the mutant form of the protein retains the ability to function in tissues typically affected by BBS. Click here to read entire article REFERENCES Harnett J.D., Green J.S., Cramer B.C., Johnson G., Chafe L., McManamon P., Farid N.R., Pryse-Phillips W., Parfrey P.S. The spectrum of renal disease in Laurence-Moon-Biedl syndrome. N. Engl. J. Med. 1988;319:615–618. doi: 10.1056/NEJM198809083191005. Green J.S., Parfrey P.S., Harnett J.D., Farid N.R., Cramer B.C., Johnson G., Heath O., McManamon P.J., O'Leary E., Pryse-Phillips W. The cardinal manifestations of Bardet-Biedl syndrome, a form of Laurence-Moon-Biedl syndrome. N. Engl. 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Loss of BBS proteins causes anosmia in humans and defects in olfactory cilia structure and function in the mouse. Nat. Genet. 2004;36:994–998. doi: 10.1038/ng1418. Nishimura D.Y., Fath M., Mullins R.F., Searby C., Andrews M., Davis R., Andorf J.L., Mykytyn K., Swiderski R.E., Yang B., et al. Bbs2-null mice have neurosensory deficits, a defect in social dominance, and retinopathy associated with mislocalization of rhodopsin. Proc. Natl Acad. Sci. USA. 2004;101:16588–16593. doi: 10.1073/pnas.0405496101. Mykytyn K., Mullins R.F., Andrews M., Chiang A.P., Swiderski R.E., Yang B., Braun T., Casavant T., Stone E.M., Sheffield V.C. Bardet-Biedl syndrome type 4 (BBS4)-null mice implicate Bbs4 in flagella formation but not global cilia assembly. Proc. Natl Acad. Sci. USA. 2004;101:8664–8669. doi: 10.1073/pnas.0402354101. Fath M.A., Mullins R.F., Searby C., Nishimura D.Y., Wei J., Rahmouni K., Davis R.E., Tayeh M.K., Andrews M., Yang B., et al. 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- Identification and Functional Analysis of the Vision-Specific BBS3 (ARL6) Long Isoform
Pamela R. Pretorius, Lisa M. Baye, Darryl Y. Nishimura, Charles C. Searby, Kevin Bugge, Baoli Yang, Robert F. Mullins, Edwin M. Stone, Val C. Sheffield, Diane C. Slusarski | March 19, 2010 | https://doi.org/10.1371/journal.pgen.1000884 Abstract Bardet-Biedl Syndrome (BBS) is a heterogeneous syndromic form of retinal degeneration. We have identified a novel transcript of a known BBS gene, BBS3 ( ARL6 ), which includes an additional exon. This transcript, BBS3L, is evolutionally conserved and is expressed predominantly in the eye, suggesting a specialized role in vision. Using antisense oligonucleotide knockdown in zebrafish, we previously demonstrated that bbs3 knockdown results in the cardinal features of BBS in zebrafish, including defects to the ciliated Kupffer's Vesicle and delayed retrograde melanosome transport. Unlike bbs3 , knockdown of bbs3L does not result in Kupffer's Vesicle or melanosome transport defects, rather its knockdown leads to impaired visual function and mislocalization of the photopigment green cone opsin. Moreover, BBS3L RNA, but not BBS3 RNA, is sufficient to rescue both the vision defect as well as green opsin localization in the zebrafish retina. In order to demonstrate a role for Bbs3L function in the mammalian eye, we generated a Bbs3L-null mouse that presents with disruption of the normal photoreceptor architecture. Bbs3L-null mice lack key features of previously published Bbs-null mice, including obesity. These data demonstrate that the BBS3L transcript is required for proper retinal function and organization. Author Summary Retinitis pigmentosa (RP), a disorder of retinal degeneration resulting in blindness, occurs due to mutations in dozens of different genes encoding proteins with highly diverse functions. To date, there are no effective therapies to delay or arrest retinal degeneration. RP places a large burden on affected families and on society as a whole. We have studied a syndromic form of RP known as Bardet-Biedl Syndrome (BBS), which leads to degeneration of the photoreceptor cells and is associated with non-vision abnormalities including obesity, hypertension, diabetes, and congenital abnormalities of the kidney, heart, and limbs. In this study we utilized two model systems, the zebrafish and mouse, to evaluate the function of a specific form of BBS (BBS3). We have identified a novel protein product of the BBS3 gene and demonstrated that functional and structural abnormalities of the eye occur when this form of BBS3 is absent. This finding is of significance because it indicates that BBS3 mutations can lead to non-syndromic blindness, as well as blindness associated with other clinical features. This work also indicates that treatment of BBS3 blindness will require replacement of a specific form of the BBS3 gene. Click here to read entire article
- Identification of photoreceptor genes affected by PRPF31 mutations associated with autosomal dominant retinitis pigmentosa
Daniel Mordes , Liya Yuan, Lili Xu, Mariko Kawada, Robert S. Molday, Jane Y. Wu | National Library of Medicine | 2007 March 9 | Vol. 26, Issue 2 | 291–300 | doi:10.1016/j.nbd.2006.08.026 Introduction Retinitis pigmentosa (RP), a common cause of blindness, is a group of inherited diseases characterized by the loss of photoreceptor cells. More than a hundred genetic loci have been associated with retinal degeneration ( Baehr and Chen, 2001 ; Swaroop and Zack, 2002 ; see websites: www.sph.uth.tmc.edu/RetNet and www.uwcm.ac.uk/uwcm/mg ). As a genetically heterogeneous disease, RP displays all three modes of Mendelian inheritance: autosomal dominant (adRP), autosomal recessive (arRP) and X-linked (xlRP). Many RP genes are expressed specifically or predominantly in the retina. Recently, four adRP genes have been identified that are ubiquitously expressed in different tissues and associated with RNA processing. Three of these non-retina-specific adRP genes encode proteins essential for pre-mRNA splicing, pre-mRNA processing factors (PRPF), including PRPF31 (or PRP31; for RP11, Vithana et al, 2001 ), PRPF8 (PRP8 or PRPC8; for RP13, McKie, 2001 ) and PRPF3 (or HPRP3; for RP18, Chakarova, 2002 ). Another adRP gene, PAP1 (for RP9), has also been implicated in pre-mRNA splicing (Maita et al., 2004 and 2005 ). Among these, PRPF31 has been reported as the second most common adRP gene, only second to the rhodopsin gene ( Vithana et al, 1998 ). An interesting question is how mutations in ubiquitously expressed pre-mRNA splicing factor genes such as PRPF31 cause photoreceptor-specific disease. Most mammalian transcription units contain at least one intron that must be removed by a process known as pre-mRNA splicing to form functional messenger RNA (mRNA). As the most upstream step of post-transcriptional regulation, pre-mRNA splicing is critical for mammalian gene expression. Pre-mRNA splicing employs a two-step transesterification mechanism. The first step involves cleavage at the 5′ splice site and formation of a lariat intermediate. The second step is cleavage at the 3′ splice site with concomitant ligation of the 5′ and 3′ exons. The sites of cleavage and ligation are defined by conserved cis -elements including the 5′ splice site (5′ss), the branch point sequence, the polypyrimidine tract and the 3′ splice site (3′ss) consensus sequence. The splicing reaction occurs in spliceosomes, the large RNA-protein complexes that contain pre-mRNA, five small nuclear ribonucleoprotein (snRNP) particles, U1, U2, U4/U6 and U5, as well as a number of non-snRNP protein factors ( Burge et. al., 1999 ; Hastings and Krainer 2001 ; Zhou et al., 2002 ; Wu et al., 2004 ). Following the initial recognition of splice sites by U1snRNP and U2snRNP together with early-step protein factors, the assembly and incorporation of the U4/U6.U5 tri-snRNP is crucial for the formation of the catalytically active center in the spliceosome. A number of proteins, including PRPF3, PRPF8 or PRPF31, play important roles in the formation tri-snRNP and assembly of the mature spliceosome. These splicing factors are highly conserved through evolution, from yeast to mammals. Originally identified in a screen for splicing defects, yeast prp31 is an essential gene encoding a 60 kDa protein. It assists in recruiting the U4/U6.U5 tri-snRNP to prespliceosome complexes and is critical for pre-mRNA splicing ( Maddock et al., 1996 ; Weidenhammer et al. 1996 , 1997 ). Mammalian PRPF3, PRPF8 or PRPF31 proteins likely play similar roles in pre-mRNA splicing as their yeast counterparts. However, it is not clear how mutations in these splicing factors lead to photoreceptor cell death and retinal degeneration. Here we describe our efforts to identify downstream “target” genes for PRPF31 using a combined molecular and biochemical approach. Immunoprecipitation of PRPF31 containing ribonucleoprotein complex followed by microarray led to the identification of 146 RNA transcripts, including several known adRP genes. We focused on RDS and FSCN2, two photoreceptor-specific genes linked to adRP, to further test effects of PRPF31 on splicing. Co-transfection of adRP mutants of PRPF31 with a minigene of RDS or FSCN2 indicated that mutant PRPF31 proteins inhibit the pre-mRNA splicing of RDS and FSCN2 genes. Expression of the mutant PRPF31 proteins led to a significant reduction in RDS expression in cultured retinal cells. These experiments show that mutations in PRPF31 inhibit pre-mRNA splicing of certain genes expressed in photoreceptor cells. Our study reveals a functional relationship between the general splicing factor, PRPF31, and expression of photoreceptor-specific genes, RDS and FSCN2. Taken together, these observations demonstrate that PRPF31 plays an important role in the pre-mRNA splicing of a subset of photoreceptor-specific genes. Click here to read entire article
- Structural Variants Create New Topological-Associated Domains and Ectopic Retinal Enhancer-Gene Contact in Dominant Retinitis Pigmentosa
Suzanne E. de Bruijn, Alessia Fiorentino, Daniele Ottaviani, Stephanie Fanucchi, Uira S. Melo, Julio C. Corral-Serrano, Timo Mulders, Michalis Georgiou, Carlo Rivolta, Nikolas Pontikos, Gavin Arno, Lisa Roberts, Jacquie Greenberg, Silvia Albert, Christian Gilissen, Marco Aben, George Rebello, Simon Mead, F. Lucy Raymond, Jordi Corominas, Claire E.L. Smith, Hannie Kremer, Susan Downes, Graeme C. Black, Andrew R. Webster, Chris F. Inglehearn, L. Ingeborgh van den Born, Robert K. Koenekoop, Michel Michaelides, Raj S. Ramesar, Carel B. Hoyng, Stefan Mundlos, Musa M. Mhlanga, Frans P.M. Cremers, Michael E. Cheetham, Susanne Roosing, and Alison J. Hardcastle, American Journal of Human Genetics | Vol 107 | p. 802–814 | 5 Nov 2020 https://www.cell.com/ajhg/pdfExtended/S0002-9297(20)30322-0 Article Summary After thirty years of research, the genetic defect that causes the eye disease retinitis pigmentosa type 17 (RP17) has finally been discovered. Molecular geneticists Susanne Roosing and Suzanne de Bruijn located the gene defect by examining the genetic material (DNA) of a large Dutch family that had been forwarded by physicians from the Department of Ophthalmology. Summary The cause of autosomal-dominant retinitis pigmentosa (adRP), which leads to loss of vision and blindness, was investigated in families lacking a molecular diagnosis. A refined locus for adRP on Chr17q22 (RP17) was delineated through genotyping and genome sequencing, leading to the identification of structural variants (SVs) that segregate with disease. Eight different complex SVs were characterized in 22 adRP-affected families with >300 affected individuals. All RP17 SVs had breakpoints within a genomic region spanning YPEL2 to LINC01476. To investigate the mechanism of disease, we reprogrammed fibroblasts from affected individuals and controls into induced pluripotent stem cells (iPSCs) and differentiated them into photoreceptor precursor cells (PPCs) or retinal organoids (ROs). Hi-C was performed on ROs, and differential expression of regional genes and a retinal enhancer RNA at this locus was assessed by qPCR. The epigenetic landscape of the region, and Hi-C RO data, showed that YPEL2 sits within its own topologically associating domain (TAD), rich in enhancers with binding sites for retinal transcription factors. The Hi-C map of RP17 ROs revealed creation of a neo-TAD with ectopic contacts between GDPD1 and retinal enhancers, and modeling of all RP17 SVs was consistent with neo-TADs leading to ectopic retinal-specific enhancer-GDPD1 accessibility. qPCR confirmed increased expression of GDPD1 and increased expression of the retinal enhancer that enters the neo-TAD. Altered TAD structure resulting in increased retinal expression of GDPD1 is the likely convergent mechanism of disease, consistent with a dominant gain of function. Our study highlights the importance of SVs as a genomic mechanism in unsolved Mendelian diseases. Read more, click here
- Mutation analysis in 129 genes associated with other forms of retinal dystrophy
157 families with retinitis pigmentosa based on exome sequencing Yan Xu, Liping Guan, Xueshan Xiao, Jianguo Zhang, Shiqiang Li, Hui Jiang, Xiaoyun Jia, Jianhua Yang, Xiangming Guo, Ye Yin, Jun Wang, and Qingjiong Zhang | Molecular Vision | 2015 Apr 28 | Vol 21 | p ages 477-86 | PMID: 25999675; PMCID: PMC4415588. Purpose Mutations in 60 known genes were previously identified by exome sequencing in 79 of 157 families with retinitis pigmentosa (RP). This study analyzed variants in 129 genes associated with other forms of hereditary retinal dystrophy in the same cohort. Introduction Retinitis pigmentosa (RP, OMIM 268000 ) is the most common and highly heterogeneous genetic group of hereditary retinal degeneration diseases, affecting one in about 3,500–5,000 individuals worldwide [ 1 - 3 ]. So far, mutations in over 60 genes have been reported to be responsible for about half of nonsyndromic RP. Phenotypic and molecular genetic overlap has been observed in different forms of retinal degeneration; for example, RP might be the main sign of syndromic RP or other related diseases. Mutations in a few genes have been shown to cause different forms of retinal dystrophy, while a few genes originally held responsible for other forms of retinal dystrophy have been found to cause RP as well. Systematic analysis of all genes responsible for other forms of retinal dystrophy in patients with RP is limited, especially in Chinese cohorts. Therefore, systemic evaluation of the frequency of mutations in all genes responsible for other forms of retinal dystrophy, apart from known RP genes, would be valuable. Our previous whole exome sequencing study detected potential pathogenic mutations in 73 known genes in 86 of 157 patients with RP. Due to the highly heterogeneous and genetically and clinically complicated features of RP, mutations in the genes related to more severe or syndromic diseases might be ignored, and mutations in previously analyzed genes might be mistakenly used in molecular diagnosis and clinical evaluation. Therefore, it might be interested to know if mutations in genes associated with other forms of retinal dystrophy may also contribute to RP. In the present study, variants in 129 genes responsible for other forms of retinal dystrophy were analyzed based on the exome data set of the same cohort of 157 patients. Read more
- A clinical and molecular characterisation of CRB1-associated maculopathy
Kamron N. Khan, Anthony Robson, Omar A. R. Mahroo, Gavin Arno, Chris F. Inglehearn, Monica Armengol, Naushin Waseem, Graham E. Holder, Keren J. Carss, Lucy F. Raymond, Andrew R. Webster, Anthony T. Moore, Martin McKibbin, Maria M. van Genderen, James A. Poulter, Michel Michaelides & UK Inherited Retinal Disease Consortium | European Journal of Human Genetics | 2018 | Vol 26 | 687–694 | Abstract To date, over 150 disease-associated variants in CRB1 have been described, resulting in a range of retinal disease phenotypes including Leber congenital amaurosis and retinitis pigmentosa. Despite this, no genotype–phenotype correlations are currently recognised. We performed a retrospective review of electronic patient records to identify patients with macular dystrophy due to bi-allelic variants in CRB1. In total, seven unrelated individuals were identified. The median age at presentation was 21 years, with a median acuity of 0.55 decimalised Snellen units (IQR = 0.43). The follow-up period ranged from 0 to 19 years (median = 2.0 years), with a median final decimalised Snellen acuity of 0.65 (IQR = 0.70). Fundoscopy revealed only a subtly altered foveal reflex, which evolved into a bull’s-eye pattern of outer retinal atrophy. Optical coherence tomography identified structural changes—intraretinal cysts in the early stages of disease, and later outer retinal atrophy. Genetic testing revealed that one rare allele (c.498_506del, p.(Ile167_Gly169del)) was present in all patients, with one patient being homozygous for the variant and six being heterozygous. In trans with this, one variant recurred twice (p.(Cys896Ter)), while the four remaining alleles were each observed once (p.(Pro1381Thr), p.(Ser478ProfsTer24), p.(Cys195Phe) and p.(Arg764Cys)). These findings show that the rare CRB1 variant, c.498_506del, is strongly associated with localized retinal dysfunction. The clinical findings are much milder than those observed with bi-allelic, loss-of-function variants in CRB1, suggesting this in-frame deletion acts as a hypomorphic allele. This is the most prevalent disease-causing CRB1 variant identified in the non-Asian population to date. Introduction To date, more than 150 disease-associated variants in CRB1 (OMIM #604210) have been described, associated with a range of inherited retinal disease (IRD) phenotypes including Leber Congenital Amaurosis (LCA), early as well as adult-onset retinitis pigmentosa (RP)—with and without a Coats-like vasculopathy, and more recently macular dystrophy and foveal schisis [ 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 ]. Characteristic features of CRB1-associated retinopathy include early onset maculopathy, loss of retinal lamination with increased retinal thickness, nummular intraretinal pigmentation, preservation of the para-arteriolar retinal pigment epithelium, and the presence of macular cysts [ 12 ]. 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