Search

Lulin Huang, Qi Zhang, Xin Huang, Chao Qu, Shi Ma, Yao Mao, Jiyun Yang, You Li, Yuanfeng Li, Chang Tan, Peiquan Zhao, Zhenglin Yang |  Scientific Reports | Vol 7 | pg. 1948 | 16 May 2017 | doi.org/10.1038/s41598-017-00963-6 Abstract Retinitis pigmentosa (RP) is highly heterogeneous in both clinical and genetic fields. Accurate mutation screening is very beneficial in improving clinical diagnosis and gene-specific treatment of RP patients. The reason for the difficulties in genetic diagnosis of RP is that the ethnic-specific mutation databases that contain both clinical and genetic information are largely insufficient. In this study, we recruited 98 small Han Chinese families clinically diagnosed as RP, including of 22 dominant, 19 recessive, 52 sporadic, and five X-linked. We then used whole exome sequencing (WES) analysis to detect mutations in the genes known for RP in 101 samples from these 98 families. In total, we identified 57 potential pathogenic mutations in 40 of the 98 (41%) families in 22 known RP genes, including 45 novel mutations. We detected mutations in 13 of the 22 (59%) typical autosomal dominant families, 8 of the 19 (42%) typical autosomal recessive families, 16 of the 52 (31%) sporadic small families, and four of the five (80%) X-linked families. Our results extended the mutation spectrum of known RP genes in Han Chinese, thus making a contribution to RP gene diagnosis and the pathogenetic study of RP genes. Introduction Retinitis pigmentosa (RP, OMIM#268,000) is caused by abnormalities of the photoreceptors (rods and cones) or the retinal pigment epithelium (RPE) of the retina, and results in progressive vision loss 1 . RP is an inherited degenerative eye disease that causes severe vision damage and often results in blindness 1 . Affected individuals may experience difficulties in light-to-dark and dark-to-light adaptation or night blindness at the early stage of RP. RP is likely the most common type of retinal dystrophy. The worldwide prevalence of non-syndromic RP is approximately 1 in 4000 2 . The prevalence of non-syndromic RP in China had been reported at 1 in 3800 3 . RP exhibits autosomal dominant (adRP), autosomal recessive (arRP), or X-linked (xlRP) models. In very rare cases, the cause is a digenic pattern of inheritance. Non-systemic RP represents about 70–80% of all cases 4 . Autosomal dominant, autosomal recessive, and X-linked account for approximately 30–40%, 50–60%, and 5–15% respectively of patients with RP 2 . Approximately 30% are sporadic cases 4 , most of which may belong to the autosomal recessive inheritance group. RP genetics are complicated and heterogeneous. To date, 27 autosomal dominant, 58 autosomal recessive, and three X-linked RP genes have been identified in the RetNet database ( http://www.sph.uth.tmc.edu/retnet/ ). Among these genes, six— BEST1 , NR2E3 , NRL , RHO , RP1 , and RPE65— can cause both autosomal dominant and autosomal recessive RP. In addition, mutations in several genes, including ABCA4 5 , PROM1 6 , PRPH2 7 , C8orf37 8 , and PRPF31 9 , can cause both RP and macular degeneration. Because of the highly genetic heterogeneity of RP, an accurate genetic diagnosis is needed to improve clinical diagnosis 10 . In recent years, whole exome sequencing (WES) has been used for the molecular diagnosis of Mendelian diseases 11 . Although similar studies in RP have been published in the last few years, most of these reports were focused on the Caucasian population. Published RP mutations in the Chinese population are rare in the Human Gene Mutation Database (HGMD, http://www.hgmd.org/ ) and the Online Mendelian Inheritance in Man (OMIM, http://omim.org/ ). Different populations may have different mutation spectra, which is very important in studying the origin and pathogenesis of heterogeneous diseases such as RP. In this study, we investigated the mutations of known RP genes in 101 patients in 98 small Han Chinese RP families, which is beneficial for RP gene diagnosis and the pathogenic study of RP. Click here to read entire article References Hamel, C. Retinitis pigmentosa. Orphanet J Rare Dis 1, 40 (2006). Hartong, D. T., Berson, E. L. & Dryja, T. P. Retinitis pigmentosa. Lancet 368, 1795–1809 (2006). Hu, D. N. Prevalence and mode of inheritance of major genetic eye diseases in China. Journal of Medical Genetics. 24, 584–588 (1987). Ferrari, S. et al . Retinitis pigmentosa: genes and disease mechanisms. Curr Genomics 12, 238–249 (2011). Sun, H., Smallwood, P. M. & Nathans, J. Biochemical defects in ABCR protein variants associated with human retinopathies. Nat Genet 26, 242–246 (2000). Yang, Z. et al . Mutant prominin 1 found in patients with macular degeneration disrupts photoreceptor disk morphogenesis in mice. J Clin Invest 118, 2908–2916 (2008). Ali, R. R. et al . Restoration of photoreceptor ultrastructure and function in retinal degeneration slow mice by gene therapy. Nat Genet 25, 306–310 (2000). van Huet, R. A. et al . Clinical characteristics of rod and cone photoreceptor dystrophies in patients with mutations in the C8orf37 gene. Invest Ophthalmol Vis Sci 54, 4683–4690 (2013). Lu, F. et al . A novel PRPF31 mutation in a large Chinese family with autosomal dominant retinitis pigmentosa and macular degeneration. PLoS One 8, e78274 (2013). Wang, X. et al . Comprehensive molecular diagnosis of 179 Leber Congenital Amaurosis and juvenile retinitis pigmentosa patients by targeted next generation sequencing. Journal of medical genetic (2013). Srivastava, S. et al . Clinical whole exome sequencing in child neurology practice. Annals of neurology 76, 473–483 (2014).

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

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

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. [ DOI ] [ PubMed ] [ Google Scholar ] Burgess R., Millar I.D., Leroy B.P. Biallelic mutation of BEST1 causes a distinct retinopathy in humans. Am. J. Hum. Genet. 2008;82:19–31. doi: 10.1016/j.ajhg.2007.08.004. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] Yardley J., Leroy B.P., Hart-Holden N. Mutations of VMD2 splicing regulators cause nanophthalmos and autosomal dominant vitreoretinochoroidopathy (ADVIRC) Investig. Ophthalmol. Vis. Sci. 2004;45:3683–3689. doi: 10.1167/iovs.04-0550. [ DOI ] [ PubMed ] [ Google Scholar ] Davidson A.E., Millar I.D., Urquhart J.E. Missense mutations in a retinal pigment epithelium protein, bestrophin-1, cause retinitis pigmentosa. Am. J. Hum. Genet. 2009;85:581–592. doi: 10.1016/j.ajhg.2009.09.015. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] Leroy B.P. Bestrophinopathies. In: Traboulsi E.I., editor. Genetic Diseases of the Eye. second ed. Oxford Univ. Press; New York: 2012. p. 434. [ 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 ]

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. J. Med. 1989;321:1002–1009. doi: 10.1056/NEJM198910123211503. Bardet G. On congenital obesity syndrome with polydactyly and retinitis pigmentosa (a contribution to the study of clinical forms of hypophyseal obesity). 1920. Obes. Res. 1995;3:387–399. doi: 10.1002/j.1550-8528.1995.tb00165.x. Biedl A. A pair of siblings with adiposo-genital dystrophy. 1922. Obes. Res. 1995;3:404. doi: 10.1002/j.1550-8528.1995.tb00167.x. Elbedour K., Zucker N., Zalzstein E., Barki Y., Carmi R. Cardiac abnormalities in the Bardet-Biedl syndrome: echocardiographic studies of 22 patients. Am. J. Med. Genet. 1994;52:164–169. doi: 10.1002/ajmg.1320520208. Riise R. Visual function in Laurence-Moon-Bardet-Biedl syndrome. A survey of 26 cases. Acta Ophthalmol. Suppl. 1987;182:128–131. doi: 10.1111/j.1755-3768.1987.tb02610.x. Leys M.J., Schreiner L.A., Hansen R.M., Mayer D.L., Fulton A.B. Visual acuities and dark-adapted thresholds of children with Bardet-Biedl syndrome. Am. J. Ophthalmol. 1988;106:561–569. doi: 10.1016/0002-9394(88)90586-7. Jacobson S.G., Borruat F.X., Apathy P.P. Patterns of rod and cone dysfunction in Bardet-Biedl syndrome. Am. J. Ophthalmol. 1990;109:676–688. doi: 10.1016/s0002-9394(14)72436-5. Fulton A.B., Hansen R.M., Glynn R.J. Natural course of visual functions in the Bardet-Biedl syndrome. Arch. Ophthalmol. 1993;111:1500–1506. doi: 10.1001/archopht.1993.01090110066026. Carmi R., Elbedour K., Stone E.M., Sheffield V.C. Phenotypic differences among patients with Bardet-Biedl syndrome linked to three different chromosome loci. Am. J. Med. Genet. 1995;59:199–203. doi: 10.1002/ajmg.1320590216. Beales P.L., Warner A.M., Hitman G.A., Thakker R., Flinter F.A. Bardet-Biedl syndrome: a molecular and phenotypic study of 18 families. J. Med. Genet. 1997;34:92–98. doi: 10.1136/jmg.34.2.92. Riise R., Andreasson S., Borgastrom M.K., Wright A.F., Tommerup N., Rosenberg T., Tornqvist K. Intrafamilial variation of the phenotype in Bardet-Biedl syndrome. Br. J. Ophthalmol. 1997;81:378–385. doi: 10.1136/bjo.81.5.378. Heon E., Westall C., Carmi R., Elbedour K., Panton C., Mackeen L., Stone E.M., Sheffield V.C. Ocular phenotypes of three genetic variants of Bardet-Biedl syndrome. Am. J. Med. Genet. A. 2005;132:283–287. doi: 10.1002/ajmg.a.30466. Katsanis N., Beales P.L., Woods M.O., Lewis R.A., Green J.S., Parfrey P.S., Ansley S.J., Davidson W.S., Lupski J.R. Mutations in MKKS cause obesity, retinal dystrophy and renal malformations associated with Bardet-Biedl syndrome. Nat. Genet. 2000;26:67–70. doi: 10.1038/79201. Slavotinek A.M., Stone E.M., Mykytyn K., Heckenlively J.R., Green J.S., Heon E., Musarella M.A., Parfrey P.S., Sheffield V.C., Biesecker L.G. Mutations in MKKS cause Bardet-Biedl syndrome. Nat. Genet. 2000;26:15–16. doi: 10.1038/79116. Nishimura D.Y., Searby C.C., Carmi R., Elbedour K., Van Maldergem L., Fulton A.B., Lam B.L., Powell B.R., Swiderski R.E., Bugge K.E., et al. Positional cloning of a novel gene on chromosome 16q causing Bardet-Biedl syndrome (BBS2) Hum. Mol. Genet. 2001;10:865–874. doi: 10.1093/hmg/10.8.865. Mykytyn K., Braun T., Carmi R., Haider N.B., Searby C.C., Shastri M., Beck G., Wright A.F., Iannaccone A., Elbedour K., et al. Identification of the gene that, when mutated, causes the human obesity syndrome BBS4. Nat. Genet. 2001;28:188–191. doi: 10.1038/88925. Mykytyn K., Nishimura D.Y., Searby C.C., Shastri M., Yen H.J., Beck J.S., Braun T., Streb L.M., Cornier A.S., Cox G.F., et al. Identification of the gene (BBS1) most commonly involved in Bardet-Biedl syndrome, a complex human obesity syndrome. Nat. Genet. 2002;31:435–438. doi: 10.1038/ng935. Ansley S.J., Badano J.L., Blacque O.E., Hill J., Hoskins B.E., Leitch C.C., Kim J.C., Ross A.J., Eichers E.R., Teslovich T.M., et al. Basal body dysfunction is a likely cause of pleiotropic Bardet-Biedl syndrome. Nature. 2003;425:628–633. doi: 10.1038/nature02030. Badano J.L., Ansley S.J., Leitch C.C., Lewis R.A., Lupski J.R., Katsanis N. Identification of a novel Bardet-Biedl syndrome protein, BBS7, that shares structural features with BBS1 and BBS2. Am. J. Hum. Genet. 2003;72:650–658. doi: 10.1086/368204. Chiang A.P., Nishimura D., Searby C., Elbedour K., Carmi R., Ferguson A.L., Secrist J., Braun T., Casavant T., Stone E.M., et al. Comparative genomic analysis identifies an ADP-ribosylation factor-like gene as the cause of Bardet-Biedl syndrome (BBS3) Am. J. Hum. Genet. 2004;75:475–484. doi: 10.1086/423903. Fan Y., Esmail M.A., Ansley S.J., Blacque O.E., Boroevich K., Ross A.J., Moore S.J., Badano J.L., May-Simera H.,, Compton D.S., et al. Mutations in a member of the Ras superfamily of small GTP-binding proteins causes Bardet-Biedl syndrome. Nat. Genet. 2004;36:989–993. doi: 10.1038/ng1414. Li J.B., Gerdes J.M., Haycraft C.J., Fan Y., Teslovich T.M., May-Simera H., Li H., Blacque O.E., Li L., Leitch C.C., et al. Comparative genomics identifies a flagellar and basal body proteome that includes the BBS5 human disease gene. Cell. 2004;117:541–552. doi: 10.1016/s0092-8674(04)00450-7. Nishimura D.Y., Swiderski R.E., Searby C.C., Berg E.M., Ferguson A.L., Hennekam R., Merin S., Weleber R.G., Biesecker L.G., Stone E.M., et al. Comparative genomics and gene expression analysis identifies BBS9, a new Bardet-Biedl syndrome gene. Am. J. Hum. Genet. 2005;77:1021–1033. doi: 10.1086/498323. Stoetzel C., Laurier V., Davis E.E., Muller J., Rix S., Badano J.L., Leitch C.C., Salem N., Chouery E., Corbani S., et al. BBS10 encodes a vertebrate-specific chaperonin-like protein and is a major BBS locus. Nat. Genet. 2006;38:521–524. doi: 10.1038/ng1771. Chiang A.P., Beck J.S., Yen H.J., Tayeh M.K., Scheetz T.E., Swiderski R.E., Nishimura D.Y., Braun T.A., Kim K.Y., Huang J., et al. Homozygosity mapping with SNP arrays identifies TRIM32, an E3 ubiquitin ligase, as a Bardet-Biedl syndrome gene (BBS11) Proc. Natl Acad. Sci. USA. 2006;103:6287–6292. doi: 10.1073/pnas.0600158103. Stoetzel C., Muller J., Laurier V., Davis E.E., Zaghloul N.A., Vicaire S., Jacquelin C., Plewniak F., Leitch C.C., Sarda P., et al. Identification of a novel BBS gene (BBS12) highlights the major role of a vertebrate-specific branch of chaperonin-related proteins in Bardet-Biedl syndrome. Am. J. Hum. Genet. 2007;80:1–11. doi: 10.1086/510256. Leitch C.C., Zaghloul N.A., Davis E.E., Stoetzel C., Diaz-Font A., Rix S., Alfadhel M., Lewis R.A., Eyaid W., Banin E., et al. Hypomorphic mutations in syndromic encephalocele genes are associated with Bardet-Biedl syndrome. Nat. Genet. 2008;40:443–448. doi: 10.1038/ng.97. Kulaga H.M., Leitch C.C., Eichers E.R., Badano J.L., Lesemann A., Hoskins B.E., Lupski J.R., Beales P.L., Reed R.R., Katsanis N. 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. Mkks-null mice have a phenotype resembling Bardet-Biedl syndrome. Hum. Mol. Genet. 2005;14:1109–1118. doi: 10.1093/hmg/ddi123. Davis R.E., Swiderski R.E., Rahmouni K., Nishimura D.Y., Mullins R.F., Agassandian K., Philp A.R., Searby C.C., Andrews M.P., Thompson S., et al. A knockin mouse model of the Bardet-Biedl syndrome 1 M390R mutation has cilia defects, ventriculomegaly, retinopathy, and obesity. Proc. Natl Acad. Sci. USA. 2007;104:19422–19427. doi: 10.1073/pnas.0708571104. Yen H.J., Tayeh M.K., Mullins R.F., Stone E.M., Sheffield V.C., Slusarski D.C. Bardet-Biedl syndrome genes are important in retrograde intracellular trafficking and Kupffer's vesicle cilia function. Hum. Mol. Genet. 2006;15:667–677. doi: 10.1093/hmg/ddi468. Tayeh M.K., Yen H.J., Beck J.S., Searby C.C., Westfall T.A., Griesbach H., Sheffield V.C., Slusarski D.C. Genetic interaction between Bardet-Biedl syndrome genes and implications for limb patterning. Hum. Mol. Genet. 2008;17:1956–1967. doi: 10.1093/hmg/ddn093. Blacque O.E., Reardon M.J., Li C., McCarthy J., Mahjoub M.R., Ansley S.J., Badano J.L., Mah A.K., Beales P.L., Davidson W.S., et al. Loss of C. elegans BBS-7 and BBS-8 protein function results in cilia defects and compromised intraflagellar transport. Genes Dev. 2004;18:1630–1642. doi: 10.1101/gad.1194004. Pereiro I., Valverde D., Pineiro-Gallego T., Baiget M., Borrego S., Ayuso C., Searby C., Nishimura D. New mutations in BBS genes in small consanguineous families with Bardet-Biedl syndrome: detection of candidate regions by homozygosity mapping. Mol. Vis. 2010;16:137–143. Pretorius P.R., Baye L.M., Nishimura D.Y., Searby C.C., Bugge K., Yang B., Mullins R.F., Stone E.M., Sheffield V.C., Slusarski D.C. Identification and functional analysis of the vision-specific BBS3 (ARL6) long isoform. PLoS Genet. 2010;6:e1000884. doi: 10.1371/journal.pgen.1000884. Abu Safieh L., Aldahmesh M., Shamseldin H., Hashem M., Shaheen R., Alkuraya H., Hazzaa S., Al-Rajhi A., Alkuraya F. Clinical and molecular characterization of Bardet-Biedl syndrome in consanguineous populations: the power of homozygosity mapping. J. Med. Genet. 2010;47:236–241. doi: 10.1136/jmg.2009.070755. Aldahmesh M.A., Safieh L.A., Alkuraya H., Al-Rajhi A., Shamseldin H., Hashem M., Alzahrani F., Khan A.O., Alqahtani F., Rahbeeni Z., et al. Molecular characterization of retinitis pigmentosa in Saudi Arabia. Mol. Vis. 2009;15:2464–2469.

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

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

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

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 ]. Expression of the retinal phenotype, however, is variable, even within families, and a number of either genetic or environmental factors have been postulated [ 13 ]. Click here to read article REFERENCES Clark GR, Crowe P, Muszynska D, et al. Development of a diagnostic genetic test for simplex and autosomal recessive retinitis pigmentosa. Ophthalmology. 2010;117:2169–77.e2163. doi: 10.1016/j.ophtha.2010.02.029. den Hollander AI, ten Brink JB, de Kok YJ, et al. Mutations in a human homologue of Drosophila crumbs cause retinitis pigmentosa (RP12) Nat Genet. 1999;23:217–21. doi: 10.1038/13848. Lotery AJ, Jacobson SG, Fishman GA, et al. Mutations in the CRB1 gene cause Leber congenital amaurosis. Arch Ophthalmol. 2001;119:415–20. doi: 10.1001/archopht.119.3.415. Lotery AJ, Malik A, Shami SA, et al. CRB1 mutations may result in retinitis pigmentosa without para-arteriolar RPE preservation. Ophthalmic Genet. 2001;22:163–9. doi: 10.1076/opge.22.3.163.2222. den Hollander AI, Davis J, van der Velde-Visser SD, et al. CRB1 mutation spectrum in inherited retinal dystrophies. Hum Mutat. 2004;24:355–69. doi: 10.1002/humu.20093. - DOI - PubMed Henderson RH, Mackay DS, Li Z, et al. Phenotypic variability in patients with retinal dystrophies due to mutations in CRB1. Br J Ophthalmol. 2011;95:811–7. doi: 10.1136/bjo.2010.186882. - DOI - PubMed Tsang SH, Burke T, Oll M, et al. Whole exome sequencing identifies CRB1 defect in an unusual maculopathy phenotype. Ophthalmology. 2014;121:1773–82. doi: 10.1016/j.ophtha.2014.03.010. - DOI - PMC - PubMed Wolfson Y, Applegate CD, Strauss RW, Han IC, Scholl HP. CRB1-related maculopathy with cystoid macular edema. JAMA Ophthalmol. 2015;133:1357–60. doi: 10.1001/jamaophthalmol.2015.2814. - DOI - PubMed Shah N, Damani MR, Zhu XS, et al. Isolated maculopathy associated with biallelic CRB1 mutations. Ophthalmic Genet. 2016;38:1–4. - PubMed Vincent A, Ng J, Gerth-Kahlert C, et al. Biallelic mutations in CRB1 underlie autosomal recessive familial foveal retinoschisis. Invest Ophthalmol Vis Sci. 2016;57:2637–46. doi: 10.1167/iovs.15-18281. - DOI - PubMed den Hollander AI, Heckenlively JR, van den Born LI, et al. Leber congenital amaurosis and retinitis pigmentosa with coats-like exudative vasculopathy are associated with mutations in the crumbs homologue 1 (CRB1) gene. Am J Hum Genet. 2001;69:198–203. doi: 10.1086/321263. - DOI - PMC - PubMed Ehrenberg M, Pierce EA, Cox GF, Fulton AB. CRB1: one gene, many phenotypes. Semin Ophthalmol. 2013;28:397–405. doi: 10.3109/08820538.2013.825277. - DOI - PubMed Bujakowska K, Audo I, Mohand-Said S, et al. CRB1 mutations in inherited retinal dystrophies. Hum Mutat. 2012;33:306–15. doi: 10.1002/humu.21653. - DOI - PMC - PubMed den Hollander AI, Ghiani M, de Kok YJ, et al. Isolation of Crb1, a mouse homologue of Drosophila crumbs, and analysis of its expression pattern in eye and brain. Mech Dev. 2002;110:203–7. doi: 10.1016/S0925-4773(01)00568-8. - DOI - PubMed Gosens I, den Hollander AI, Cremers FP, Roepman R. Composition and function of the Crumbs protein complex in the mammalian retina. Exp Eye Res. 2008;86:713–26. doi: 10.1016/j.exer.2008.02.005. - DOI - PubMed Pocha SM, Knust E. Complexities of Crumbs function and regulation in tissue morphogenesis. Curr Biol. 2013;23:R289–293. doi: 10.1016/j.cub.2013.03.001. - DOI - PubMed Alves CH, Pellissier LP, Vos RM, et al. Targeted ablation of Crb2 in photoreceptor cells induces retinitis pigmentosa. Hum Mol Genet. 2014;23:3384–401. doi: 10.1093/hmg/ddu048. - DOI - PubMed Alves CH, Pellissier LP, Wijnholds J. The CRB1 and adherens junction complex proteins in retinal development and maintenance. Prog Retin Eye Res. 2014;40:35–52. doi: 10.1016/j.preteyeres.2014.01.001. - DOI - PubMed Cho SH, Kim JY, Simons DL, et al. Genetic ablation of Pals1 in retinal progenitor cells models the retinal pathology of Leber congenital amaurosis. Hum Mol Genet. 2012;21:2663–76. doi: 10.1093/hmg/dds091. - DOI - PMC - PubMed Pellikka M, Tanentzapf G, Pinto M, et al. Crumbs, the Drosophila homologue of human CRB1/RP12, is essential for photoreceptor morphogenesis. Nature. 2002;416:143–9. doi: 10.1038/nature721. - DOI - PubMed Mehalow AK, Kameya S, Smith RS, et al. CRB1 is essential for external limiting membrane integrity and photoreceptor morphogenesis in the mammalian retina. Hum Mol Genet. 2003;12:2179–89. doi: 10.1093/hmg/ddg232. - DOI - PubMed Bach M, Brigell MG, Hawlina M, et al. ISCEV standard for clinical pattern electroretinography (PERG): 2012 update. Doc Ophthalmol. 2013;126:1–7. doi: 10.1007/s10633-012-9353-y. - DOI - PubMed McCulloch DL, Marmor MF, Brigell MG, et al. ISCEV standard for full-field clinical electroretinography (2015 update) Doc Ophthalmol. 2015;130:1–12. doi: 10.1007/s10633-014-9473-7. - DOI - PubMed Ellingford JM, Barton S, Bhaskar S, et al. Molecular findings from 537 individuals with inherited retinal disease. J Med Genet. 2016;53:103838. doi: 10.1136/jmedgenet-2016-103837. - DOI - PMC - PubMed Carss KJ, Arno G, Erwood M, et al. Comprehensive rare variant analysis via whole-genome sequencing to determine the molecular pathology of inherited retinal disease. Am J Hum Genet. 2017;100:75–90. doi: 10.1016/j.ajhg.2016.12.003. - DOI - PMC - PubMed Corton M, Tatu SD, Avila-Fernandez A, et al. High frequency of CRB1 mutations as cause of early-onset retinal dystrophies in the Spanish population. Orphanet J Rare Dis. 2013;8:20. doi: 10.1186/1750-1172-8-20. - DOI - PMC - PubMed Sanchez-Alcudia R, Corton M, Avila-Fernandez A, et al. Contribution of mutation load to the intrafamilial genetic heterogeneity in a large cohort of Spanish retinal dystrophies families. Invest Ophthalmol Vis Sci. 2014;55:7562–71. doi: 10.1167/iovs.14-14938. - DOI - PubMed Motta FL, Salles MV, Costa KA, Filippelli-Silva R, Martin RP, Sallum JMF. The correlation between CRB1 variants and the clinical severity of Brazilian patients with different inherited retinal dystrophy phenotypes. Sci Rep. 2017;7:8654. doi: 10.1038/s41598-017-09035-1. - DOI - PMC - PubMed Pellissier LP, Quinn PM, Alves CH, et al. Gene therapy into photoreceptors and Muller glial cells restores retinal structure and function in CRB1 retinitis pigmentosa mouse models. Hum Mol Genet. 2015;24:3104–18. doi: 10.1093/hmg/ddv062. - DOI - PubMed Assemat E, Crost E, Ponserre M, Wijnholds J, Le Bivic A, Massey-Harroche D. The multi-PDZ domain protein-1 (MUPP-1) expression regulates cellular levels of the PALS-1/PATJ polarity complex. Exp Cell Res. 2013;319:2514–25. doi: 10.1016/j.yexcr.2013.07.011. - DOI - PubMed Bulgakova NA, Kempkens O, Knust E. Multiple domains of Stardust differentially mediate localisation of the Crumbs-Stardust complex during photoreceptor development in Drosophila. J Cell Sci. 2008;121:2018–26. doi: 10.1242/jcs.031088. - DOI - PubMed Michel D, Arsanto JP, Massey-Harroche D, Beclin C, Wijnholds J, Le Bivic A. PATJ connects and stabilizes apical and lateral components of tight junctions in human intestinal cells. J Cell Sci. 2005;118:4049–57. doi: 10.1242/jcs.02528. - DOI - PubMed Ali M, Hocking PM, McKibbin M, et al. Mpdz null allele in an avian model of retinal degeneration and mutations in human leber congenital amaurosis and retinitis pigmentosa. Invest Ophthalmol Vis Sci. 2011;52:7432–40. doi: 10.1167/iovs.11-7872. - DOI - PubMed Jaron R, Rosenfeld N, Zahdeh F, et al. Expanding the phenotype of CRB2 mutations - a new ciliopathy syndrome? Clin Genet. 2016;90:540–4. doi: 10.1111/cge.12764. - DOI - PubMed Lamont RE, Tan WH, Innes AM, et al. Expansion of phenotype and genotypic data in CRB2-related syndrome. Eur J Hum Genet. 2016;24:1436–44. doi: 10.1038/ejhg.2016.24. - DOI - PMC - PubMed Slavotinek A, Kaylor J, Pierce H, et al. CRB2 mutations produce a phenotype resembling congenital nephrosis, Finnish type, with cerebral ventriculomegaly and raised alpha-fetoprotein. Am J Hum Genet. 2015;96:162–9. doi: 10.1016/j.ajhg.2014.11.013. - DOI - PMC - PubMed Charbel Issa P, Gillies MC, Chew EY, et al. Macular telangiectasia type 2. Prog Retin Eye Res. 2013;34:49–77. doi: 10.1016/j.preteyeres.2012.11.002. - DOI - PMC - PubMed Zhao M, Andrieu-Soler C, Kowalczuk L, et al. A new CRB1 rat mutation links Muller glial cells to retinal telangiectasia. J Neurosci. 2015;35:6093–106. doi: 10.1523/JNEUROSCI.3412-14.2015. - DOI - PMC - PubMed Parry DA, Toomes C, Bida L, et al. Loss of the metalloprotease ADAM9 leads to cone-rod dystrophy in humans and retinal degeneration in mice. Am J Hum Genet. 2009;84:683–91. doi: 10.1016/j.ajhg.2009.04.005. - DOI - PMC - PubMed Hull S, Arno G, Robson AG, et al. Characterization of CDH3-related congenital hypotrichosis with juvenile macular dystrophy. JAMA Ophthalmol. 2016;134:992–1000. doi: 10.1001/jamaophthalmol.2016.2089. - DOI - PubMed Aleman TS, Cideciyan AV, Aguirre GK, et al. Human CRB1-associated retinal degeneration: comparison with the rd8 Crb1-mutant mouse model. Invest Ophthalmol Vis Sci. 2011;52:6898–910. doi: 10.1167/iovs.11-7701. - DOI - PMC - PubMed

Retinitis pigmentosa research probes role of the enzyme DHDDS in this genetic disease BIRMINGHAM, Ala. - Researchers who made a knock-in mouse-model of the genetic disorder retinitis pigmentosa 59, or RP59, expected to see retinal degeneration and retinal thinning. As reported in the journal Cells , they surprisingly found none, calling into question the commonly accepted -- though never proved -- mechanism for RP59. "Our findings bring into question the current concept that RP59 is a member of a large and diverse class of diseases known as 'congenital disorders of glycosylation,'" said Steven Pittler, Ph.D., professor and director of the University of Alabama at Birmingham School of Optometry and Vision Science Vision Science Research Center. "While in principle it would be reasonable to consider RP59 as a congenital disorder of glycosylation, due to the associated mutation in DHDDS, an enzyme required for glycosylation, there is no direct evidence to demonstrate a glycosylation defect in the human retinal disease or in any animal model of RP59 generated to date." Read more

Jonas Kuiper, Prof. dr. Dr Saskia Imhof, Prof. dr. Dr. Joke de Boer, Prof. dr. Dr Mies van Genderen, Prof. dr. Dr Tim Radstake | July 30, 2020 Research Retinal death can be caused by several genes. When there is an error in the CRB1 gene, some people become severely visually impaired. Others with the same gene mutation experience fewer vision problems. The reason for this may be due to the immune system. This is what we investigate in this study. The retina is the innermost part (the inner lining) of the eye. This consists of many different cells, whereby the rods and the cones (the photoreceptors) ensure the reception and transmission of a light signal. The rods are specialized in seeing contrast (dark and light) and the cones in seeing colors. Retinal dystrophy is an umbrella term that means nothing less than a 'disorder of the retina'. A common form of retinal dystrophy is retinitis pigmentosa , a condition that prevents the rods from functioning properly. The rods, but also the cones, eventually break down and cause a chain reaction. This causes visibility to deteriorate over the years. Read the original post. Interested in participating? UMC Utrecht asks that you contact: drs. Lude Moekotte, physician-researcher E-mail: l.moekotte@umcutrecht.nl Telephone number: +31 088 75 719 33 It is not certain that you can participate after registration. The study doctor first assesses, based on the medical data, whether you meet all the criteria for participation.

Published: Jan 26, 2022 | UCI School Of Medicine Researchers from the University of California, Irvine have discovered that the absence of Adiponectin receptor 1 protein (AdipoR1), one of the principal enzymes regulating ceramide homeostasis in the retina, leads to an accumulation of ceramides in the retina, resulting in progressive photoreceptor cell death and ultimately vision loss. The team also found that a combination of desipramine and L-cycloserine reduced lowered ceramide levels, which protected photoreceptors, helped preserve the retina’s structure and function, and improved vision. The study, titled “Inhibition of ceramide accumulation in  AdipoR1-/-  mice increases photoreceptor survival and improves vision,” was published this month in the  Journal of Clinical Investigation Insight . Study findings show that ceramide imbalance damages the neural retina and retinal pigmented epithelium, accompanied by a significant reduction of electroretinogram amplitudes, decreased retinoid content in the retina, reduced cone opsin expression and massive inflammatory response. A buildup of ceramides in the retina, likely due to insufficient ceramidase activity, led to photoreceptor death. When treated with the desipramine and L-cycloserine combination, ceramide levels were lowered, which helped preserve photoreceptors in mice. The team also observed improved daylight vision in the L-cycloserine treated mice, and that prolonged treatment significantly improved electrical responses of the primary visual cortex to visual stimuli. “Although AdipoR1 is found in multiple organs, the highest levels are found in the eye and brain, suggesting its critical importance in these neural tissues." Although AdipoR1 is found in multiple organs, the highest levels are found in the eye and brain, suggesting its critical importance in these neural tissues. Our study results highlight the significance of AdipoR1 ceramides in the retina, and show that pharmacological inhibition of ceramide generation can provide a therapeutic strategy for patients suffering from retinitis pigmentosa or AdipoR1-related retinopathies,” said  Krzysztof Palczewski, PhD , Donald Bren Professor of Ophthalmology at the UCI School of Medicine and co-corresponding author. click here to read entire article