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with mutations in PDE6A and PDE6B Samer Khateb, MD, PhD | Marco Nassisi, MD | Kinga M. Bujakowska, PhD | Cécile Méjécase, MSc | Christel Condroyer, MSc | Aline Antonio, BA | Marine Foussard, BA | Vanessa Démontant, BA | Saddek Mohand-Saïd, MD, PhD | José-Alain Sahel, MD | Christina Zeitz, PhD | Isabelle Audo, MD, PhD | JAMA Ophthalmol | 2019 Apr 18 | 137(6) | 669-679 | doi:10.1001/jamaophthalmol.2018.6367 Key Points Question What are the functional and structural changes over time of patients with rod-cone dystrophy harboring mutations in PDE6A and PDE6B? Findings In this cohort, longitudinal, follow-up study of 54 patients with rod-cone dystrophy and mutations in PDE6A or PDE6B, progressive photoreceptor degeneration was documented. The findings reveal a similar disease course between both genetic groups with preservation of functional visual abilities at older ages. Meaning The results of this study suggest that these functional and structural findings may enable a better prognostic estimation and candidate selection for photoreceptor therapeutic rescue. Abstract Importance A precise phenotypic characterization of retinal dystrophies is needed for disease modeling as a basis for future therapeutic interventions. Objective To compare genotype, phenotype, and structural changes in patients with rod-cone dystrophy (RCD) associated with mutations in PDE6A or PDE6B. To read more of the source article, click here.

Peng Yong Sim, V Swetha E Jeganathan, Alan F. Wright, Peter Cackett | 2018 Summary This case report depicts the clinical course of a female patient with unilateral retinitis pigmentosa, who first presented at the age of 12 years. Fundus photography at the time revealed unilateral pigmentary retinopathy, which was associated with extinguished electroretinogram (ERG) signal. At 35 years of age, fundus examination revealed deterioration of pre-existing unilateral pigmentary retinopathy with progressive visual field defect detected on Goldmann visual field testing. ERG findings remained unchanged and multifocal ERG showed unilateral decrease in amplitude in the affected eye. The patient was referred for genetic counselling. Next-generation sequencing identified a deleterious heterozygous c.118T>G (p.Cys40Gly) mutation in the CLRN1 gene. To read the full article, it must be purchased for $294. See link for details

"FDA Approves Gene Therapy for Inherited Blindness Developed by the University of Pennsylvania and Children’s Hospital of Philadelphia" | PennMedicine News Decision marks the first gene therapy approved for a genetic disease in the U.S. PHILADELPHIA – In a historic move, the U.S. Food and Drug Administration (FDA) today approved a gene therapy initially developed by researchers at the University of Pennsylvania and Children’s Hospital of Philadelphia (CHOP) for the treatment of a rare, inherited form of retinal blindness. The decision marks the nation’s first gene therapy approved for the treatment of a genetic disease, and the first in which a new, corrective gene is injected directly into a patient. The therapy, known as LUXTURNA™ (voretigene neparvovec-ryzl), significantly improves eyesight in patients with confirmed biallelic RPE65 mutation-associated retinal dystrophy. Patients with RPE65 mutations suffer from severe visual impairment at infancy or early childhood, and by mid-life become totally blind. They previously had no pharmacologic treatment options. Spark Therapeutics, a Philadelphia biotechnology company created in 2013 by CHOP in an effort to accelerate the timeline for bringing new gene therapies to market, led the late-stage clinical development of LUXTURNA and built in West Philadelphia the first licensed manufacturing facility in the U.S. for a gene therapy treating an inherited disease. Spark was built on the foundational research conducted over a ten-year period by CHOP’s Center for Cellular and Molecular Therapeutics (CCMT). Those efforts were led by Jean Bennett, MD, PhD, the F.M. Kirby professor of Ophthalmology at the Perelman School of Medicine at the University of Pennsylvania and Penn’s Scheie Eye Institute, and Katherine A. High, MD, who directed the CCMT and now serves as Spark’s president and head of research and development. Albert M. Maguire, MD, a professor of Ophthalmology at the Perelman School of Medicine and an attending physician at CHOP, served as the principal investigator of the clinical trials which led to today’s FDA approval. Read entire press release

Tisiana Low, Anastassios Kostakis, Meena Balasubramanian |  Ophthalmic Genetics  | Nov 7 2017 | Vol 39, Issue 2 | pgs. 286-287 | doi/full/10.1080/13816810.2017.1393827 Introduction Retinitis pigmentosa (RP) refers to a group of inherited disorders that affect the retina’s ability to respond to light, leading to progressive visual loss. Retinitis pigmentosa sine pigmento is a variant of RP in which there is an absence of characteristic peripheral bone-spicule like pigmentary changes. One of the genes found to be responsible for RP is IFT140, a ciliary transporter gene (OMIM *614620). Homozygous and compound heterozygous IFT140 variants have commonly been reported in Mainzer-Saldino syndrome and Jeune syndrome(1). However, in recent literature, non-syndromic IFT140-related RP have been reported. IFT140 encodes a sub-unit of intraflagellar transport complex A (IFTA), which is involved in retrograde ciliary transport(2). It was previously referred to as KIAA0590 and located on chromosome 16p13.3. It is highly expressed in kidneys with moderate expression in ovary, testis, lung, prostate. Schmidts et al., 2013 demonstrated high expression of Ift140 in renal and retinal tissue in mouse embryos(3). Although the phenotype associated with IFT140 variants is still emerging, it appears to encompass a variable spectrum ranging from non-syndromic, isolated RP (as demonstrated in this clinical report) to Short-rib thoracic dysplasia 9 with or without polydactyly (SRTD9; OMIM # 266920). Case Report We present a case of a 22-year-old female who attended her opticians for a frequent headaches review. It was found that her visual fields were restricted, with a slightly abnormal retina with greying and mottling (Fig 1). However, night-time vision was not reduced. An optical coherence tomography suggested likely RP, and electrodiagnostic testing confirmed the diagnosis. She was the first child of healthy, non-consanguineous, White European parents and had a younger sister who was fit and well with no family history of RP. A recent ophthalmology follow-up review found that the patient had visual acuities of 6/6 with patchy visual defects in bilateral eyes, but no significant decrease in visual fields. Click here to purchase the article References Bifari IN, Elkhamary SM, Bolz HJ, et al. The ophthalmic phenotype of IFT140- related ciliopathy ranges from isolated to syndromic congenital retinal dystrophy. Br J Ophthalmology. 2015; 0:1-5. Perrault I, Saunier S, Hanein S, et al. Mainzer-Saldino Syndrome Is a Ciliopathy Caused by IFT140 Mutations. Am J Hum Genet. 2012; 90(5):864–870. Schmidts M, Frank V, Eisenberger T, et al. Combined NGS Approaches Identify Mutations in the Intraflagellar Transport Gene IFT140 in Skeletal Ciliopathies with Early Progressive Kidney Disease. Hum Mutat. 2013; 34(5):714–724. Hull S, Owen N, Islam F, et al. Nonsyndromic retinal dystrophy due to bi-allelic mutations in the ciliary transport gene IFT140. Invest Ophthalmol Vis Sci. 2016; 57:1053–1062. Neveling K, Collin R, Gilissen C, et al. Next-generation genetic testing for retinitis pigmentosa. Hum Mutat. 2012; 33(6):963-972.

and underlies severe Usher syndrome on the Arabian Peninsula Arif O. Khan, Elvir Becirovic, Christian Betz, Christine Neuhaus, Janine Altmüller, Lisa Maria Riedmayr, Susanne Motameny, Gudrun Nürnberg, Peter Nürnberg & Hanno J. Bolz | Scientific Reports | Vol. 7, Article # 1411 | 2017 May 03 | Abstract Deafblindness is mostly due to Usher syndrome caused by recessive mutations in the known genes. Mutation-negative patients therefore either have distinct diseases, mutations in yet unknown Usher genes or in extra-exonic parts of the known genes – to date a largely unexplored possibility. In a consanguineous Saudi family segregating Usher syndrome type 1 (USH1), NGS of genes for Usher syndrome, deafness and retinal dystrophy and subsequent whole-exome sequencing each failed to identify a mutation. Genome-wide linkage analysis revealed two small candidate regions on chromosome 3, one containing the USH3A gene CLRN1, which has never been associated with Usher syndrome in Saudi Arabia. Whole-genome sequencing (WGS) identified a homozygous deep intronic mutation, c.254–649T > G, predicted to generate a novel donor splice site. CLRN1 minigene-based analysis confirmed the splicing of an aberrant exon due to usage of this novel motif, resulting in a frameshift and a premature termination codon. We identified this mutation in an additional two of seven unrelated mutation-negative Saudi USH1 patients. Locus-specific markers indicated that c.254–649T > G CLRN1 represents a founder allele that may significantly contribute to deafblindness in this population. Our finding underlines the potential of WGS to uncover atypically localized, hidden mutations in patients who lack exonic mutations in the known disease genes. Introduction Usher syndrome is the most common cause of inherited deafblindness1. Type 1 (USH1) is characterized by congenital deafness and early (first decade) retinitis pigmentosa (RP), whereas type 2 (USH2) displays progressive hearing impairment and RP of later onset. USH3 is characterized by progressive hearing loss, RP, and variable peripheral vestibular dysfunction2. However, disease resulting from mutations in the USH3A gene, CLRN1, is variable, ranging from non-syndromic RP3 to USH14. The advent of next-generation sequencing (NGS) has enabled panel-sequencing of the 11 known Usher genes, and its application in a recent study on European deafblind patients identified the causative mutations in the majority5. In a Saudi Arabian family with four siblings affected by Usher syndrome type 1, escalating the genetic investigations from gene panel NGS over genome-wide linkage analysis to whole-exome sequencing (WES) and finally whole-genome sequencing (WGS) led up to the molecular diagnosis. Our study demonstrates the potential of WGS to unlock hidden mutations. Results NGS of gene panels for retinal dystrophy and for deafness Apart from a heterozygous frameshift mutation in TUBGCP6, c.5001_5003delinsCA (p.Gln1667Hisfs*11), NGS of the known genes for Usher syndrome, for other syndromic and isolated hearing loss, and for retinal degeneration did not identify any mutations. Biallelic TUBGCP6 mutations cause microcephalic primordial dwarfism and additional congenital anomalies, including retinopathy6. Given the recessive inheritance and additional symptoms associated with mutations in TUBGCP6 (which are not present in the affected family members analyzed in our study), the apparently monoallelic variant most likely represents carriership for an unrelated disorder. Our results from NGS panel analysis thus largely excluded not only mutations in the coding sequences of the Usher syndrome genes and genes causing similar syndromes (e.g. USH3-like PHARC due to ABHD12 mutations7), but also simultaneous mutations in a deafness gene and an RP gene mimicking Usher syndrome. Quantitative analysis of NGS reads did not indicate large copy number variations (CNVs) such as deletions of one or several contiguous exons. Read the entire article References Mathur, P. & Yang, J. Usher syndrome: Hearing loss, retinal degeneration and associated abnormalities. Biochim Biophys Acta 1852, 406–420, doi:10.1016/j.bbadis.2014.11.020 (2015). Ness, S. L. et al. Genetic homogeneity and phenotypic variability among Ashkenazi Jews with Usher syndrome type III. J Med Genet 40, 767–772, doi:10.1136/jmg.40.10.767 (2003). Khan, M. I. et al. CLRN1 mutations cause nonsyndromic retinitis pigmentosa. Ophthalmology 118, 1444–1448, doi:10.1016/j.ophtha.2010.10.047 (2011). Ebermann, I. et al. Deafblindness in French Canadians from Quebec: a predominant founder mutation in the USH1C gene provides the first genetic link with the Acadian population. Genome Biol 8, R47, doi:10.1186/gb-2007-8-4-r47 (2007). Bonnet, C. et al. An innovative strategy for the molecular diagnosis of Usher syndrome identifies causal biallelic mutations in 93% of European patients. Eur J Hum Genet 24, 1730–1738, doi:10.1038/ejhg.2016.99 (2016). Martin, C. A. et al. Mutations in PLK4, encoding a master regulator of centriole biogenesis, cause microcephaly, growth failure and retinopathy. Nat Genet 46, 1283–1292, doi:10.1038/ng.3122 (2014). Eisenberger, T. et al. Targeted next-generation sequencing identifies a homozygous nonsense mutation in ABHD12, the gene underlying PHARC, in a family clinically diagnosed with Usher syndrome type 3. Orphanet J Rare Dis 7, 59, doi:10.1186/1750-1172-7-59 (2012).

A deep intronic CLRN1 (USH3A) founder mutation generates an aberrant exon and underlies severe Usher syndrome on the Arabian Peninsula Abstract Deaf blindness is mostly due to Usher syndrome caused by recessive mutations in the known genes. Mutation-negative patients therefore either have distinct diseases, mutations in yet unknown Usher genes or in extra-exonic parts of the known genes – to date a largely unexplored possibility. In a consanguineous Saudi family segregating Usher syndrome type 1 (USH1), NGS of genes for Usher syndrome, deafness and retinal dystrophy and subsequent whole-exome sequencing each failed to identify a mutation. Genome-wide linkage analysis revealed two small candidate regions on chromosome 3, one containing the USH3A gene CLRN1, which has never been associated with Usher syndrome in Saudi Arabia. Whole-genome sequencing (WGS) identified a homozygous deep intronic mutation, c.254–649T > G, predicted to generate a novel donor splice site. CLRN1 minigene-based analysis confirmed the splicing of an aberrant exon due to usage of this novel motif, resulting in a frameshift and a premature termination codon. We identified this mutation in an additional two of seven unrelated mutation-negative Saudi USH1 patients. Locus-specific markers indicated that c.254–649T > GCLRN1represents a founder allele that may significantly contribute to deaf blindness in this population. Our finding underlines the potential of WGS to uncover atypically localized, hidden mutations in patients who lack exonic mutations in the known disease genes. Read more.

Royal National Institute of Blind People (RNIB) "Retinitis pigmentosa (RP) is the name given to a group of inherited eye conditions called retinal dystrophies." "A retinal dystrophy such as RP affects the retina at the back of your eye and, over time, stops it from working. This means that RP causes gradual but permanent changes that reduce your vision. How much of your vision is lost, how quickly this happens and your age when it begins depends on the type of RP that you have. The changes in your vision happen over years rather than months, and some people lose more sight than others." Living with RP - Dave's Story - RNIB Series To read more, click here.

Wenyan Xu, Miaomiao Jin, Ruikun Hu, Hong Wang, Fan Zhang, Shiaulou Yuan and Ying Cao | Journal of the American Society of Nephrology | January 2017 | 28 (1) | 118-129 | https://doi.org/10.1681/ASN.2015080906 Abstract Phosphoinositides, a family of phosphorylated derivatives of phosphatidylinositol (PtdIns), are tightly regulated both temporally and spatially by PtdIns phosphatases and kinases. Mutations in inositol polyphosphate 5-phosphatase E ( INPP5E ) cause Joubert syndrome, a human disorder associated with numerous ciliopathic defects, including renal cyst formation, linking phosphoinositides to ciliopathies. However, the molecular mechanism by which INPP5E-mediated PtdIns signaling regulates ciliogenesis and cystogenesis is unclear. Here, we utilized an in vivo vertebrate model of renal cystogenesis to show that Inpp5e enzymatic activity at the apical membrane directs apical docking of basal bodies in renal epithelia. Knockdown or knockout of inpp5e led to ciliogenesis defects and cystic kidneys in zebrafish. Furthermore, knockdown of inpp5e in embryos led to defects in cell polarity, cortical organization of F-actin, and apical segregation of PtdIns(4,5)P2 and PtdIns(3,4,5)P3. Knockdown of the ezrin gene, which encodes an ezrin/radixin/moesin (ERM) protein that crosslinks PtdIns(4,5)P2 and F-actin, phenocopied inpp5e knockdowns. Notably, overexpression of the ezrin gene rescued inpp5e morphants. Finally, treatment with the PI 3-kinase inhibitor LY294002, which decreases PtdIns(3,4,5)P3 levels, rescued the cellular, phenotypic, and renal functional defects in inpp5e -knockdown embryos. Together, our data indicate that Inpp5e functions as a key regulator of cell polarity in the renal epithelia, by inhibiting PtdIns(3,4,5)P3 and subsequently stabilizing PtdIns(4,5)P2 and recruiting Ezrin, F-actin, and basal bodies to the apical membrane, and suggest a possible novel approach for treating human ciliopathies.

Ga vin Arno, Keren J. Carss, Sarah Hull, Ceniz Zihni, Anthony G. Robson, Alessia Fiorentino, UK Inherited Retinal Disease Consortium, Alison J. Hardcastle, Graham E. Holder, Michael E. Cheetham, VIncent Plagnol, NIHR Bioresource - Rare Disease Consortium, Anthony T. Moore, F. Lucy Raymond, Karl Matter, Maria S. Balda, Andrew R. Webster,  Published 2017 Jan 26 | doi:  10.1016/j.ajhg.2016.12.014 Mutations in more than 250 genes are implicated in inherited retinal dystrophy; the encoded proteins are involved in a broad spectrum of pathways. The presence of unsolved families after highly parallel sequencing strategies suggests that further genes remain to be identified. Whole-exome and -genome sequencing studies employed here in large cohorts READ entire article, click here Key Word: ARHGEF18

Lauren A Dalvin , Jackson Abou Chehade , John (pei wen) Chiang , Josefine Fuchs , Raymond Lezzi , Alan D Marmorstein | Investigative Ophthalmology & Visual Science | September 2016 | Vol.57 | pg. 655 | https://iovs.arvojournals.org/article.aspx?articleid=2559455 Purpose Mutations in BEST1 are associated with 5 clinically distinct diseases, commonly referred to as the bestrophinopathies. The bestrophinopathies include adult onset vitelliform dystrophy (AVMD), Best vitelliform macular dystrophy (BVMD), autosomal recessive bestrophinopathy (ARB), autosomal dominant vitreoretinochoroidopathy (ADVIRC), and retinitis pigmentosa (RP). Only one study has identified mutations in BEST1 associated with retinitis pigmentosa (RP), and the findings described in that study were atypical of RP with some features of ADVIRC or ARB. Here we report a new subject with RP apparently due to a novel deletion mutation in BEST1. Methods A 16-year-old male was referred from Denmark with poor visual acuity, visual field loss, and cystoid macular edema. Clinical examination, visual field testing, optical coherence tomography (OCT), OCT angiography (OCTA), electroretinography, and electrooculography were used to confirm the classic RP phenotype. Genetic testing of the proband and both parents was carried out by the University of Oregon, Casey Eye Institute, Molecular Diagnostic Laboratory using a panel of 131 retinal dystrophy genes. Results The proband, but not his parents were found to exhibit a classical RP phenotype, which included extensive bone spicules and cystoid macular edema in the presence of generalized visual field constriction, depressed rod and cone electroretinogram (ERG) responses, and reduced Arden ratios on electrooculogram (EOG). A novel heterozygous deletion of 9348 bases (61729891-61733239) from the BEST1 gene resulting in the mutation H422fsX431 was identified in the proband but not in either parent. The deletion begins within exon 10 of the BEST1 gene and extends beyond exon 11 resulting in a frame shift causing deletion of 146aa from Best1, and extending into the adjacent ferritin heavy chain (FTH) gene on the opposite strand of DNA. The proband did not exhibit any symptoms of ferritin deficiency. Conclusions BEST1 mutations play a role in some cases of RP. However, it is difficult to understand why some mutations associate with peripheral retinal degeneration phenotypes like RP and ADVIRC, while others manifest as macular degeneration phenotypes. The identification of additional cases of RP associated with a deletion in BEST1 should improve our ability to elucidate the differential pathogenesis of the 5 bestrophinopathies. This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016 . Click here to read more.

By Raquel Perez-Carro, Marta Corton, Iker Sánchez-Navarro, Olga Zurita, Noelia Sanchez-Bolivar, Rocío Sánchez-Alcudia, Stefan H. Lelieveld, Elena Aller, Miguel Angel Lopez-Martinez, Mª Isabel López-Molina, Patricia Fernandez-San Jose, Fiona Blanco-Kelly, Rosa Riveiro-Alvarez, Christian Gilissen, Jose M Millan, Almudena Avila-Fernandez & Carmen Ayuso | Article number: 19531 | 2016 Abstract Retinitis pigmentosa (RP) is a group of inherited progressive retinal dystrophies (RD) characterized by photoreceptor degeneration. RP is highly heterogeneous both clinically and genetically, which complicates the identification of causative genes and mutations. Targeted next-generation sequencing (NGS) has been demonstrated to be an effective strategy for the detection of mutations in RP. In our study, an in-house gene panel comprising 75 known RP genes was used to analyze a cohort of 47 unrelated Spanish families pre-classified as autosomal recessive or isolated RP. Disease-causing mutations were found in 27 out of 47 cases achieving a mutation detection rate of 57.4%. In total, 33 pathogenic mutations were identified, 20 of which were novel mutations (60.6%). Furthermore, not only single nucleotide variations but also copy-number variations, including three large deletions in the USH2A and EYS genes, were identified. Finally seven out of 27 families, displaying mutations in the ABCA4, RP1, RP2 and USH2A genes, could be genetically or clinically reclassified. These results demonstrate the potential of our panel-based NGS strategy in RP diagnosis. Introduction Retinitis pigmentosa (RP, MIM 268000) is the most common form of inherited retinal degeneration with a prevalence of 1 in 4000 individuals. RP is characterized by primary rod degeneration leading to night blindness, the development of tunnel vision and slow progressive decrease in central vision. However, the disease onset, progression, retinal appearance and final visual outcome may vary significantly among patients, even within the same family. RP is also a highly heterogeneous genetic disorder; the disease can be inherited in different forms including autosomal dominant (adRP) in about 20-40% of the cases, autosomal recessive (arRP) in 30-50% or X-linked trait (xlRP) in 5-15% of the cases. Sporadic cases (sRP) account for about 40% of all diagnoses, although these percentages vary between different populations. Non-Mendelian inheritance patterns such as digenic, mitochondrial or de novo mutations have been also reported, though these account for a minor proportion of cases. Read the article.

Jun Yin, Jan Brocher, Utz Fischer, Christoph Winkler  | Molecular Neurodegeneration | Vol. 6, Issue 56 | 2011 | doi.org/10.1186/1750-1326-6-56 Summary RP mutations have also been identified in a group of housekeeping genes that are involved in pre-mRNA splicing and represent the second-largest contribution to RP after mutations in rhodopsin. These genes include  PRPF3, PRPF8, PRPF31 ,  PAP1  and  SNRN200 . All these genes encode core components of the U4/U6.U5 tri-snRNP complex which constitutes a major building block of the pre-mRNA processing spliceosome. Background Retinitis pigmentosa (RP) is an inherited eye disease characterized by the progressive degeneration of rod photoreceptor cells. Mutations in pre-mRNA splicing factors including PRPF31 have been identified as cause for RP, raising the question how mutations in general factors lead to tissue specific defects. Results We have recently shown that the zebrafish serves as an excellent model allowing the recapitulation of key events of RP. Here we use this model to investigate two pathogenic mutations in PRPF31 , SP117 and AD5, causing the autosomal dominant form of RP. We show that SP117 leads to an unstable protein that is mislocalized to the rod cytoplasm. Importantly, its overexpression does not result in photoreceptor degeneration suggesting haploinsufficiency as the underlying cause in human RP patients carrying SP117. In contrast, overexpression of AD5 results in embryonic lethality, which can be rescued by wild-type Prpf31. Transgenic retina-specific expression of AD5 reveals that stable AD5 protein is initially localized in the nucleus but later found in the cytoplasm concurrent with progressing rod outer segment degeneration and apoptosis. Importantly, we show for the first time in vivo that retinal transcripts are wrongly spliced in adult transgenic retinas expressing AD5 and exhibiting increased apoptosis in rod photoreceptors. Conclusion Our data suggest that distinct mutations in Prpf31 can lead to photoreceptor degeneration through different mechanisms, by haploinsufficiency or dominant-negative effects. Analyzing the AD5 effects in our animal model in vivo , our data imply that aberrant splicing of distinct retinal transcripts contributes to the observed retina defects.