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Ninel Z. Gregori, MD and Mark E. Pennesi, MD, PHD | Retina Today | July/August 2024 | When you specialize in inherited retinal diseases (IRDs), it can be easy to lose perspective of how rare these conditions are. Those of us who manage IRDs see these patients frequently and routinely spot clinical signs of retinitis pigmentosa (RP), classic Stargardt disease, and Leber congenital amaurosis (LCA). However, even these more common conditions do not present to all retina practices often. After all, RP has a prevalence of approximately one in 4,000; that’s only 110,000 patients in the United States.1 Compare that to the nearly 20 million patients diagnosed with AMD.2 When we step away from our IRD clinics and engage with the retina community, we are reminded how uncommon these diagnoses are. However, the latest news and conferences bring IRD research and innovation into the spotlight. During one session at this year’s Atlantic Coast Retina Club, half of the case presentations were IRDs. In the first half of 2024, 16% of the news stories that ran on Eyewire+ were focused on IRDs; since January, at least 11 companies have announced updates to their IRD clinical trial programs.1,3-15 With the advent of gene and cell therapies, IRDs have become an important focus for researchers. Although voretigene neparvovec-rzyl (Luxturna, Spark Therapeutics) for RPE65 -associated LCA is the only approved genetic therapy for an IRD, many companies are working their way through clinical trials for various inherited conditions. This issue of Retina Today is an ode to the innovation happening in the IRD space. Cristy A. Ku, MD, PhD, and her team at Baylor provide a roundup of gene therapy trials (nearly 30!), while Ishrat Ahmed, MD, PhD, and Mandeep S. Singh, MD, PhD, summarize novel approaches , such as stem cell therapy, optogenetics, and retinal prosthesis. Elizabeth Kellom, MS, CGC, and Kimberly Stepien, MD, explore various genetic testing approaches and what to do if the results are inconclusive. Jonathan F. Russell, MD, PhD, and his colleagues at the University of Iowa discuss managing IRD patients who present with complications , and Kevin C. Allan, MD, PhD, and Alex Yuan, MD, PhD, look at various imaging techniques . Shima Dehghani, MD, and Stephanie M. Llop, MD, highlight clinical trials in uveitis , another rare retinal condition with a robust therapy pipeline—they touch on 16 ongoing phase 3 and 4 trials. Finally, a can’t-miss article in this issue is a mystery case compilation to test your diagnostic acumen. Although the IRD patient population is small compared with other retinal conditions, the research on novel therapeutic approaches is not. Patients with an IRD may feel isolated because of their diagnosis, yet hundreds of researchers and clinicians are working hard to bring new therapies to market. Rare , in this case, is a relative term. For those of us working in the IRD space, it doesn’t feel as if their condition is all that rare with so much buzz about genetic testing, imaging, monitoring, and (one day) treatment. We should share this enthusiasm and research momentum with our patients; if nothing else, it helps them find hope—and perhaps a clinical trial and potential cure. Click here to read source article Reference Retinitis pigmentosa. National Organization for Rare Disorders. December 9, 2021. Accessed July 2, 2024. Rein DB, Wittenborn JS, Burke-Conte Z, et al. Prevalence of age-related macular degeneration in the US in 2019. JAMA Ophthalmol . 2022;140(12):1202-1208. Ocugen doses first patient in phase 3 clinical trial for OCU400 gene therapy for RP [press release]. Eyewire+. June 20, 2024. Accessed July 1, 2024. Beacon Therapeutics treats first patient in VISTA trial of AGTC-501 for XLRP [press release]. Eyewire+. June 12, 2024. Accessed July 1, 2024. Atsena Therapeutics announces positive clinical data from the first cohort of phase 1/2 trial evaluating gene therapy for XLRS [press release]. Eyewire+. May 1, 2024. Accessed July 1, 2024. Aldeyra Therapeutics announces planned pivotal clinical trial for RP drug candidate [press release]. Eyewire+. April 26, 2024. Accessed July 1, 2024. Nanoscope announces topline results from phase 2b trial of MCO-010 for retinitis pigmentosa [press release]. Eyewire+. March 26, 2024. Accessed July 1, 2024. Opus Genetics completes dosing in first cohort of phase 1/2 trial of gene therapy OPGx-LCA5 [press release]. Eyewire+. March 26, 2024. Accessed July 1, 2024. GenSight Biologics confirms sustained efficacy and safety of Lumevoq injections 4 years after one-time administration [press release]. Eyewire+. March 20, 2024. Accessed July 1, 2024. Atsena Therapeutics initiates dosing in second cohort of phase 1/2 trial evaluating XLRS gene therapy [press release]. Eyewire+. March 13, 2024. Accessed July 1, 2024. jCyte announces pre-phase 3 type b meeting with FDA; outlines plans to start pivotal trial of jCell for RP [press release]. Eyewire+. February 24, 2024. Accessed July 1, 2024. Beacon Therapeutics announces positive 12-month data from phase 2 SKYLINE trial of AGTC-501 in patients with XLRP [press release]. Eyewire+. February 8, 2024. Accessed July 1, 2024. Alkeus Pharmaceuticals announced positive interim data showing gildeuretinol halted Stargardt disease progression for up to 6 years in the ongoing TEASE-3 clinical trial. Eyewire+. January 12, 2024. Accessed July 1, 2024. Théa acquires rights to KIO-301 for the treatment of inherited retinal diseases in $301 million deal [press release]. Eyewire+. February 1, 2024. Accessed July 1, 2024. ViGeneron announces first patient dosed in phase 1b trial of VG901 for the intravitreal treatment of RP [press release]. Eyewire+. April 10, 2024. Accessed July 1, 2024.

Sarah Hull, MA, PhD ; Marcella Attanasio ; Gavin Arno, PhD ; Keren Carss, PhD ; Anthony G. Robson, MSc, PhD ; Dorothy A. Thompson, PhD ; Vincent Plagnol, MSc, PhD ; Michel Michaelides, MD ; Graham E. Holder, MSc, PhD ; Robert H. Henderson, MD (Res) ; F. Lucy Raymond, MA ; Anthony T. Moore, MA ; Andrew R. Webster, MD (Res) | JAMA Ophthalmology | 2017 | 135(2) | pgs. 137–144 | doi:10.1001/jamaophthalmol.2016.5213 Key Points Question   What can a detailed clinical and molecular genetic study of patients with CNGB1 -related retinitis pigmentosa reveal about the disease presentation and progression? Findings   This case series of 10 patients with retinitis pigmentosa identified childhood onset of nyctalopia with preserved visual acuity and central photoreceptors into adulthood. Meaning   The findings of this case series suggest that retinitis pigmentosa due to variants in CNGB1 is slowly progressive with a long potential treatment window. Abstract Importance   There are limited published data on the phenotype of retinitis pigmentosa (RP) related to CNGB1 variants. These data are needed both for prognostic counseling of patients and for understanding potential treatment windows. Objective   To describe the detailed clinical and molecular genetic findings in a series of patients with RP with likely pathogenic variants in CNGB1. Design, Setting, and Participants   In this case series, 10 patients from 9 families underwent full ophthalmologic examination. Molecular investigations included whole-exome analysis in 6 patients. The study was conducted from April 17, 2013, to March 3, 2016, with final follow-up completed on March 2, 2016, and data were analyzed from October 27, 2014, to March 29, 2016. Main Outcomes and Measures   Results of ophthalmologic examination and molecular genetic analysis of CNGB1 . Results   In this case series, 7 women and 3 men from 9 families with a mean (SD) age of 47.4 (13.2) years identified as having CNGB1 variants were included in this study; there was a mean (SD) follow-up length of 3.7 (2.8) years. The first clinical presentation was with nyctalopia in childhood with visual field loss documented later at a mean (SD) age of 33.2 (8.0) years. All patients had preserved best-corrected visual acuity into adulthood, with a mean of 0.1 logMAR (Snellen equivalent, 20/25) in each eye (logMAR range, 0.0 to 0.3 [Snellen 20/20 to 20/40] in the right eye and −0.1 to 0.3 [Snellen 20/16 to 20/40] in the left eye). Fundus examination revealed midperipheral retinal pigment epithelial atrophy and intraretinal pigment migration. Optical coherence tomography of the macula demonstrated complete preservation of the inner segment ellipsoid band in 1 patient, with variable lateral extent in the other patients corresponding to the diameter of a paracentral ring of increased fundus autofluorescence. Electrophysiologic testing in 6 patients confirmed a rod-cone dystrophy phenotype. Molecular investigations identified a previously reported missense variant (p.[N986I]) and 7 variants not previously reported in disease including 4 nonsense (p.[(Q88*], p.[Q222*], p.[Q318*], and p.[R729*]), 2 frameshift (p.[A1048fs*13], p.[L849Afs*3]), and a splice site variant (c.761 + 2T>A). Conclusions and Relevance   The data from this study suggest that visual acuity and foveal structure in patients with RP are preserved into adult life such that a lengthy window of opportunity should exist for intervention with novel therapies. Click here to read more

Zhang, Xiao-hui, Bing Dong, Wei-yu Yan, Ming-hua Shan | PubMed | Vol.  24, Issue 6 | pages 670-3 | 2007 Dec 24 |  pubmed.ncbi.nlm.nih.gov/18067080/ Abstract Objective: To illuminate pathogenic gene and mutation in a Chinese family with autosomal dominant retinitis pigmentosa (adRP). Methods: Genetic linkage analysis was performed on the known genetic loci for adRP with a panel of polymorphic markers, and then all exons including exon-intron boundary, 5oUTR and 3oUTR of the candidate gene were sequenced directly. Results: Two-point LOD scores were negative with all markers tested except D17S701 (Zmax=2.107, theta=0) and D17S1604 (Zmax=1.806, theta=0). The disease gene locus was confined to RP17 with further genetic linkage and haplotype analysis. Screening all exons including exon-intron boundary, 5oUTR and 3oUTR of carbonic anhydrase 4 (CA4) revealed no mutation in this family. Conclusion: The disease-causing gene of one Chinese family with adRP was first mapped to RP17, however no gene mutation of CA4 was detected in this family. Maybe there is a complex CA4 gene mutation in this family or a new disease-causing gene for this family in this locus, further study need to be done. Click here to read more

Kinga Bujakowska, Isabelle Audo, Saddek Mohand-Saïd, Marie-Elise Lancelot, Aline Antonio, Aurore Germain, Thierry Léveillard, Mélanie Letexier, Jean-Paul Saraiva, Christine Lonjou, Wassila Carpentier, José-Alain Sahel, Shomi S. Bhattacharya, Christina Zeitz |  Human Mutation |  2011  Dec 27 |  Vol. 33, Issue 2 | 306–315 |   doi.org/10.1002/humu.21653 Abstract Mutations in the CRB1 gene are associated with variable phenotypes of severe retinal dystrophies, ranging from leber congenital amaurosis (LCA) to rod-cone dystrophy, also called retinitis pigmentosa (RP). Moreover, retinal dystrophies resulting from CRB1 mutations may be accompanied by specific fundus features: preservation of the para-arteriolar retinal pigment epithelium (PPRPE) and retinal telangiectasia with exudation (also referred to as Coats-like vasculopathy). In this publication, we report seven novel mutations and classify over 150 reported CRB1 sequence variants that were found in more that 240 patients. The data from previous reports were used to analyze a potential correlation between CRB1 variants and the clinical features of respective patients. This meta-analysis suggests that the differential phenotype of patients with CRB1 mutations is due to additional modifying factors rather than particular mutant allele combination. To buy full text, click here.

Scott F. Geller, Karen I. Guerin, Meike Visel, Aaron Pham, Edwin S. Lee, Amiel A. Dror, Karen B. Avraham, Toshinori Hayashi, Catherine A. Ray, Thomas A. Reh, Olivia Bermingham-McDonogh, William J. Triffo, Shaowen Bao,​ John G. Flannery | PLOS Genetics | Vol. 5(8) | 14 Aug 2009 | doi.org/10.1371/journal.pgen.1000607 Abstract Mutations in the CLRN1 gene cause Usher syndrome type 3 (USH3), a human disease characterized by progressive blindness and deafness. Clarin 1, the protein product of CLRN1 , is a four-transmembrane protein predicted to be associated with ribbon synapses of photoreceptors and cochlear hair cells, and recently demonstrated to be associated with the cytoskeleton. To study Clrn1 , we created a Clrn1 knockout (KO) mouse and characterized the histological and functional consequences of Clrn1 deletion in the retina and cochlea. Clrn1 KO mice do not develop a retinal degeneration phenotype, but exhibit progressive loss of sensory hair cells in the cochlea and deterioration of the organ of Corti by 4 months. Hair cell stereocilia in KO animals were longer and disorganized by 4 months, and some Clrn1 KO mice exhibited circling behavior by 5–6 months of age. Clrn1 mRNA expression was localized in the retina using in situ hybridization (ISH), laser capture microdissection (LCM), and RT–PCR. Retinal Clrn1 transcripts were found throughout development and adulthood by RT–PCR, although expression peaked at P7 and declined to undetectable levels in adult retina by ISH. LCM localized Clrn1 transcripts to the retinas inner nuclear layer, and WT levels of retinal Clrn1 expression were observed in photoreceptor-less retinas. Examination of Clrn1 KO mice suggests that CLRN1 is unnecessary in the murine retina but essential for normal cochlear development and function. This may reflect a redundancy in the mouse retina not present in human retina. In contrast to mouse KO models of USH1 and USH2, our data indicate that Clrn1 expression in the retina is restricted to the Müller glia. This is a novel finding, as most retinal degeneration associated proteins are expressed in photoreceptors, not in glia. If CLRN1 expression in humans is comparable to the expression pattern observed in mice, this is the first report of an inner retinal protein that, when mutated, causes retinal degeneration.

Usher Syndrome Coalition | usher-syndrome.org | Westford, MA | 800.946.9203 Mission The Usher Syndrome Coalition’s mission is to raise awareness and accelerate research for the most common genetic cause of combined deafness and blindness. The Coalition also provides information and support to individuals and families affected by Usher syndrome. Vision The Usher Syndrome Coalition aims to identify and connect the 400,000+ people living with Usher syndrome worldwide with researchers, vital information, and others in the Usher syndrome community. By bridging the gap between researchers and those impacted, we will expedite the full understanding of Usher syndrome necessary for the development of treatments for the associated vision, hearing and vestibular issues and, ultimately, a cure. History In 2008, the Usher Syndrome Coalition was founded out of a need to raise awareness for voices unheard. We began as an informal collaboration between a handful of researchers and families devoted to building a network of support for those affected, and improving communication between researchers. Today, the Usher Syndrome Coalition is the most comprehensive resource for the Usher syndrome community. The Usher Syndrome Coalition represents families on every continent and collaborates with researchers from some of the finest international organizations in the world. Resources You are not alone. Join the USH Trust to be informed of clinical trials and the latest advances in research. Join the USH Blue Book to connect with individuals with Usher syndrome, family members and friends in a global network of support. Locate experts in the USH Yellow Book , a centralized directory of researchers and resources worldwide. Visit website to learn more.

Yan Ma, Xun Wang, Nadav Shoshany, Xiaodong Jiao, Adrian Lee, Gregory Ku, Emma L. Baple, James Fasham, Raheela Nadeem, Muhammad Asif Naeem, Sheikh Riazuddin, S. Amer Riazuddin, Andrew H. Crosby, J. Fielding Hejtmancik | Frontiers in Genetics | 21 March 2022 | Vol 13 | doi.org/10.3389/fgene.2022.804924 Background A CLCC1 c. 75C > A (p.D25E) mutation has been associated with autosomal recessive pigmentosa in patients in and from Pakistan. CLCC1 is ubiquitously expressed, and knockout models of this gene in zebrafish and mice are lethal in the embryonic period, suggesting that possible retinitis pigmentosa mutations in this gene might be limited to those leaving partial activity. In agreement with this hypothesis, the mutation is the only CLCC1 mutation associated with retinitis pigmentosa to date, and all identified patients with this mutation share a common SNP haplotype surrounding the mutation, suggesting a common founder. Methods SNPs were genotyped by a combination of WGS and Sanger sequencing. The original founder haplotype, and recombination pathways were delineated by examination to minimize recombination events. Mutation age was estimated by four methods including an explicit solution, an iterative approach, a Bayesian approach and an approach based solely on ancestral segment lengths using high density SNP data. Results All members of each of the nine families studied shared a single autozygous SNP haplotype for the CLCC1 region ranging from approximately 1–3.5 Mb in size. The haplotypes shared by the families could be derived from a single putative ancestral haplotype with at most two recombination events. Based on the haplotype and Gamma analysis, the estimated age of the founding mutation varied from 79 to 196 generations, or approximately 2,000–5,000 years, depending on the markers used in the estimate. The DMLE (Bayesian) estimates ranged from 2,160 generations assuming a population growth rate of 0–309 generations assuming a population growth rate of 2% with broad 95% confidence intervals. Conclusion These results provide insight into the origin of the CLCC1 mutation in the Pakistan population. This mutation is estimated to have occurred 2000–5,000 years ago and has been transmitted to affected families of Pakistani origin in geographically dispersed locations around the world. This is the only mutation in CLCC1 identified to date, suggesting that the CLCC1 gene is under a high degree of constraint, probably imposed by functional requirements for this gene during embryonic development. Introduction Retinitis pigmentosa (RP [MIM 268000]) is a clinically and genetically heterogeneous disorder affecting approximately one in 4,000 individuals worldwide ( Hartong et al., 2006 ). Clinically, patients initially exhibit night blindness followed by progressive loss of peripheral visual fields, eventually culminating in compromise or even complete loss of central vision. Typical fundus changes include bone spicule-like pigmentation in the mid-peripheral retina, waxy pallor of the optic discs, and attenuation of retinal blood vessels. Since RP initially affects the rod photoreceptors, followed by the degeneration of cone photoreceptors, patients often have severely diminished or extinguished rod response in electroretinography (ERG) even in early stages of the disease, while the cone response is relatively preserved initially but decreases and becomes undetectable as the disease progresses ( Bird, 1995 ). Genetic inheritance patterns of RP include autosomal-dominant (about 30–40% of cases), autosomal-recessive (50–60%), and X-linked (5–15%) inheritance ( Bunker et al., 1984 ; Rivolta et al., 2002 ). More than 82 causative genes have been identified for RP so far, of which 58 genes have been identified in families with autosomal recessive RP (arRP) ( Daiger et al., 2021 ). At least in part reflecting social and economic considerations, the frequency of consanguineous marriages in Pakistan is among the highest in the world ( Bittles, 2001 ), ranging from 15 to 35% ( Hamamy et al., 2011 ). In reviewing 146 genetically resolved arRP Pakistani families, Khan et al. found only 4 (2.7%) with compound heterozygous mutations ( Khan et al., 2014 ), emphasizing the role of consanguinity on the incidence of arRP in this population. Not only does the high frequency of consanguinity in the Pakistani population bring out autosomal recessive alleles, but it also increases the likelihood that sharing of variations by different families is likely to be the result of the variant allele being derived from a common ancestor, especially if the families that share the same variation also share a common intragenic SNP haplotype for the associated gene. Chloride channel CLIC like 1 (CLCC1) is a transmembrane channel protein with high permeability for anions, in particular chloride, localized to the endoplasmic reticulum (ER) and in some cell types possibly the Golgi apparatus and Nucleus ( Nagasawa et al., 2001 ). The CLCC1 gene spans 33 kb, comprising 13 exons encoding a 551 amino acid protein. Li et al. ( Li et al., 2018 ) demonstrated that Clcc1 is highly expressed in the mouse retina, and modestly expressed in the iris, optic nerve, sclera, and cornea. Immunohistochemistry in the normal adult human eye demonstrated CLCC1 expression extensively in the retina and optic nerve, suggesting a physiologic role of CLCC1 in retinal function. Within the retina, CLCC1 staining was more intense in the lamina cribrosa, optic nerve, ganglion cell layer, inner and outer nuclear layers, and retinal pigment epithelium (RPE). The CLCC1 NM_145,543.2:c.75C > A (p.D25E) missense mutation in CLCC1 was found in seven Pakistani families and one British-Bangladeshi family with arRP mapping to chromosome 1p13 (RP32; 609,913). Recent additional screening has found one new family (61334) carrying the same mutation, bringing the total number of families to nine and accounting for about 6% of genetic cases of arRP in Pakistani families ( Li et al., 2017 ). The present study was undertaken to investigate the possible common ancestry of the nine Pakistani and Pakistani-derived families carrying the c.75C > A mutation, to define the likely recombination and mutational events that would be required to occur if they did have a common founder, to estimate the approximate age of the putative founder mutation and to correlate the history and geographic distribution of this mutation with the population history of Pakistan. To achieve these goals, we performed haplotype analysis of 99 intragenic SNPs flanking the c.75C > A CLCC1 mutation, derived the recombinational pathways requiring the fewest recombination events to yield the currently observed haplotypes, and estimated the number of generations that have occurred since the original mutation in the founder. To read entire article, click here. References Bird, A. C. (1995). Retinal Photoreceptor Dystrophies LI. Edward Jackson Memorial Lecture. Am. J. 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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

Ilaria D'Atri, Emily-Rose Martin, Liming Yang, Elizabeth Sears, Emma Baple, Andrew H. Crosby, John K. Chilton, Asami Oguro-Ando | Neuroscience Letters | Vol 830 | May 2024 | doi.org/10.1016/j.neulet.2024.137778 Abstract The endoplasmic reticulum (ER) plays an indispensable role in cellular processes, including maintenance of calcium homeostasis, and protein folding, synthesized and processing. Disruptions in these processes leading to ER stress and the accumulation of misfolded proteins can instigate the unfolded protein response (UPR), culminating in either restoration of balanced proteostasis or apoptosis. A key player in this intricate balance is CLCC1, an ER-resident chloride channel, whose essential role extends to retinal development, regulation of ER stress, and UPR. The importance of CLCC1 is further underscored by its interaction with proteins localized to mitochondria-associated endoplasmic reticulum membranes (MAMs), where it participates in UPR induction by MAM proteins. In previous research, we identified a p.(Asp25Glu) pathogenic CLCC1 variant associated with retinitis pigmentosa (RP) (CLCC1 hg38 NC_000001.11; NM_001048210.3, c.75C > A; UniprotKB Q96S66). In attempt to decipher the impact of this variant function, we leveraged liquid chromatography-mass spectrometry (LC-MS) to identify likely CLCC1-interacting proteins. We discovered that the CLCC1 interactome is substantially composed of proteins that localize to ER compartments and that the Asp25Glu variant results in noticeable loss and gain of specific protein interactors. Intriguingly, the analysis suggests that the CLCC1Asp25Glu mutant protein exhibits a propensity for increased interactions with cytoplasmic proteins compared to its wild-type counterpart. To corroborate our LC-MS data, we further scrutinized two novel CLCC1 interactors, Calnexin and SigmaR1, chaperone proteins that localize to the ER and MAMs . Through microscopy, we demonstrate that CLCC1 co-localizes with both proteins, thereby validating our initial findings. Moreover, our results reveal that CLCC1 co-localizes with SigmaR1 not merely at the ER, but also at MAMs. These findings reinforce the notion of CLCC1 interacting with MAM proteins at the ER-mitochondria interface, setting the stage for further exploration into how these interactions impact ER or mitochondria function and lead to retinal degenerative disease when impaired. Background In eukaryotes the endoplasmic reticulum (ER) is the organelle where calcium homeostasis is maintained, and lipids or proteins are produced, modified, exported, and degraded [1] , [2] , [3] . The folding of proteins is a necessary step for export or membrane insertion, and failure of this process leads to accumulation of misfolded proteins [3] , [4] . When the demand for the secretion of folded proteins and the accumulation of misfolded proteins occurs, the ER undergoes stress [4] , [5] . Pathways of stress signaling, collectively called the unfolded protein response (UPR), are activated to restore homeostasis and survival of the cell or induce apoptosis , leading to cell death [5] , [6] . Many proteins have been identified to be fundamental for retinal development and function (for example RHO, RP1 , ATF6 , CLCC1, etc.) [7] , [8] , [9] , [10] . One of these, CLCC1, is an ER-resident chloride channel , and variants in it have been associated with neurodegeneration of the retina [11] . Although the variant (referred to as the Asp25Glu variant) results in pathological events, its expression is necessary for development [7] . We have previously shown that loss of function of CLCC1 during development in both mouse and zebrafish is lethal, while heterozygous knockout or knockdown negatively impact the development of the retina [7] . Specifically, cone and rod photoreceptors fail to develop, with fewer number of them being functional [7] . As mentioned above, CLCC1 localizes in the ER, and the loss of CLCC1 was linked with increase of UPR response and ER stress [7] . CLCC1 loss of function has also been reported to increase the levels of ER chaperone BiP (GRP78), consistent with the induction of ER stress [12] . Recently, Chu et al. [13] demonstrated that CLCC1 interacts with the microprotein PIGBOS at ER-mitochondria contact sites, where CLCC1 is necessary for PIGBOS to function as an UPR activator. In this work, we looked for binding partners of CLCC1 using mass spectrometry and validate novel CLCC1-interacting proteins by immunoprecipitation and microscopy. We observe that CLCC1 co-localizes and co-precipitates with Calnexin ; as well as Sigma Non-Opioid Intracellular Receptor 1 (SigmaR1), an ER chaperone protein that localizes to mitochondria-associated endoplasmic reticulum membranes (MAMs). These results support the finding of CLCC1 interacting with MAM proteins at the interface betw een the ER and mitochondria. Click here to read entire article

Press Release" American Academy of Ophthalmology | October 20, 2024 Two-year study finds patients with advanced disease can recover some vision CHICAGO, Ill. —  New research to be presented this week at AAO 2024, the 128th annual meeting of the American Academy of Ophthalmology , suggests that a new kind of gene therapy can improve vision in people who have lost nearly all sight to retinitis pigmentosa , an inherited condition for which there is no cure and no way to stop it from advancing. While not all patients enrolled in the study responded to treatment, up to 50 percent gained three lines of vision on a standard eye chart. Researchers believe the treatment could also help patients suffering from other types of retinal degeneration. “We are finally on the brink of an impactful therapy for people with severe vision loss,” said lead researcher Allen C. Ho, MD, director of Retina Research and co-director of the Retina Service of Wills Eye Hospital. “These findings finally deliver hope to patients and ophthalmologists that something is close to being able to help them.” An estimated 1.5 million people worldwide have retinitis pigmentosa, a group of rare eye diseases that affect the retina, the light-sensitive layer of tissue in the back of the eye. The condition causes the cells responsible for sight, called photoreceptors, to break down over time, causing vision loss. It starts with loss of night vision and usually progresses to loss of color, side, and central vision. Dr. Ho and his colleagues are investigating a technique called optogenetics to target cells in the retina that don’t normally sense light but often survive after photoreceptors die. It's a one-time intravitreal injection into the eye that uses a harmless virus to deliver copies of light-sensing molecules (Multi-Characteristic Opsin gene) to the surviving cells, turning them into new light-sensing cells to replace lost photoreceptors. Unlike earlier optogenetics therapies that combined an eye injection with the use of high-tech goggles, this experimental treatment (MCO-010) doesn't require any external device or high intensity light stimulation to coax the cells to respond to light. MCO-010 is not the first gene therapy to improve vision in patients with retinitis pigmentosa. Luxturna (voretigene neparvovec) is the first FDA-approved gene therapy for retinitis pigmentosa. It works by replacing a faulty gene with a healthy one. But it only works in people who have a specific gene mutation, RPE65, which represents 0.3 to 1 percent of all retinitis pigmentosa cases. Click here to read entire press release

In females, hormones like estrogen and progesterone significantly influence protein development by regulating muscle mass, bone density, and overall metabolism, particularly during menstrual cycles and menopause, where fluctuations in hormone levels can impact protein synthesis and breakdown; adequate protein intake is crucial for maintaining hormonal balance and supporting reproductive health throughout a woman's life.  Key points about hormones and protein development in females: Estrogen's role: Estrogen promotes protein synthesis, contributing to muscle building and bone health during reproductive years.  Progesterone's influence: During the luteal phase of the menstrual cycle, progesterone levels rise, potentially impacting protein metabolism and causing slight fluctuations in appetite.  Impact on muscle mass: Fluctuations in estrogen levels, especially during menopause, can lead to muscle loss if protein intake is not sufficient.  Hormonal regulation of protein synthesis: Hormones like insulin-like growth factor-1 (IGF-1) also play a role in regulating protein synthesis throughout the body, including in muscle tissue.  How protein supports hormone balance: Amino acid building blocks: Protein is composed of amino acids, which are essential components for the synthesis of various hormones, including estrogen and progesterone.  Blood sugar stability: Adequate protein intake helps regulate blood sugar levels, which can positively impact insulin sensitivity and hormone balance.  Satiety and appetite control: Protein consumption promotes feelings of fullness, which can help manage calorie intake and prevent hormonal imbalances associated with overeating.  Important considerations: Menstrual cycle phases: Protein needs may vary slightly depending on the phase of the menstrual cycle, with potentially higher requirements during the luteal phase.  Menopause and protein intake: Postmenopausal women should focus on maintaining adequate protein intake to combat muscle loss associated with declining estrogen levels.  Dietary sources of protein: A balanced diet including lean meat, poultry, fish, eggs, dairy products, legumes, nuts, and seeds can provide the necessary amino acids for optimal hormone function. THE POST IS FOR EDUCATIONAL PURPOSES ONLY. IT IS NOT INTENDED AS A SUBSTITUTE FOR THE DIAGNOSIS, TREATMENT, AND ADVICE OF A QUALIFIED LICENSED MEDICAL PROFESSIONAL. RP HOPE ASSUMES NO RESPONSIBILITY FOR HOW THE SITE CONTENT IS USED. RP HOPE (A) DOES NOT RECOMMEND OR ENDORSE ANY MEDICAL PROFESSIONALS AND (B) DISCLAIMS ANY REPRESENTATIONS, WARRANTIES, OR LIABILITY OF ANY KIND WITH RESPECT TO ANY MEDICAL PROFESSIONAL OR THE QUALITY OF THE HEALTHCARE SERVICES HE OR SHE MAY PROVIDE

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. 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