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Carla Sanjurjo-Soriano, Nejla Erkilic, Gaël Manes, Gregor Dubois, Christian P Hamel, Isabelle Meunier, Vasiliki Kalatzis
We generated an induced pluripotent stem cell (iPSC) line from a patient with non-syndromic retinitis pigmentosa who is a compound heterozygote for the two most frequent USH2A variants, c.2276G > T and c.2299delG localized in exon 13. Patient fibroblasts were reprogrammed using the non-integrative Sendai virus reprogramming method and the human OSKM transcription factor cocktail. The generated cells were pluripotent and genetically stable. This iPSC line will be an important tool for studying the pathogenesis of these USH2A mutations and for developing treatments that, due their high prevalence, will target a large patient population...
November 10, 2018: Stem Cell Research
Fabiana Louise Motta, Renan Paulo Martin, Rafael Filippelli-Silva, Mariana Vallim Salles, Juliana Maria Ferraz Sallum
Among the Brazilian population, the frequency rates of inherited retinal dystrophies and their causative genes are underreported. To increase the knowledge about these dystrophies in our population, we retrospectively studied the medical records of 1,246 Brazilian patients with hereditary retinopathies during 20 years of specialized outpatient clinic care. Of these patients, 559 had undergone at least one genetic test. In this cohort, the most prevalent dystrophies were non-syndromic retinitis pigmentosa (35%), Stargardt disease (21%), Leber congenital amaurosis (9%), and syndromic inherited retinal dystrophies (12%)...
October 29, 2018: Scientific Reports
Marianna E Ivanova, Vladimir N Trubilin, Dmitry S Atarshchikov, Andrey M Demchinsky, Vladimir V Strelnikov, Alexander S Tanas, Olga M Orlova, Anton S Machalov, Kira V Overchenko, Tatiana V Markova, Daria M Golenkova, Kirill I Anoshkin, Ilya V Volodin, Dmitry V Zaletaev, Andrey A Pulin, Irina I Nadelyaeva, Alexey I Kalinkin, Debmalya Barh
BACKGROUND: Usher syndrome (USH) is heterogeneous in nature and requires genetic test for diagnosis and management. Mutations in USH associated genes are reported in some populations except Russians. Here, we first time represented the mutation spectrum of a Russian USH cohort. METHODS: Twenty-eight patients with USH were selected from 3214 patients from Deaf-Blind Support Foundation "Con-nection" during 2014-2016 following the observational study NCT03319524...
October 25, 2018: Ophthalmic Genetics
Stephanie J Valberg, Sudeep Perumbakkam, Erica C McKenzie, Carrie J Finno
Equine myofibrillar myopathy (MFM) causes exertional muscle pain and is characterized by myofibrillar disarray and ectopic desmin aggregates of unknown origin. To investigate the pathophysiology of MFM, we compared resting and 3 h post-exercise transcriptomes of gluteal muscle and the resting skeletal muscle proteome of MFM and control Arabian horses using RNA-sequencing and iTRAQ analyses. Three hours after exercise, 191 genes were identified as differentially expressed (DE) in MFM vs. control muscle with > 1 log2 fold change [FC] in genes involved in sulfur compound/ cysteine metabolism such as cystathionine-beta-synthase [CBS, ↓4...
October 5, 2018: Physiological Genomics
Ralph Slijkerman, Alexander Goloborodko, Sanne Broekman, Erik de Vrieze, Lisette Hetterschijt, Theo Peters, Milou Gerits, Hannie Kremer, Erwin van Wijk
The frequent deep-intronic c.7595-2144A>G mutation in intron 40 of USH2A generates a high-quality splice donor site, resulting in the incorporation of a pseudoexon (PE40) into the mature transcript that is predicted to prematurely terminate usherin translation. Aberrant USH2A pre-mRNA splicing could be corrected in patient-derived fibroblasts using antisense oligonucleotides. With the aim to study the effect of the c.7595-2144A>G mutation and USH2A splice redirection on retinal function, a humanized zebrafish knockin model was generated, in which 670 basepairs of ush2a intron 40 were exchanged for 557 basepairs of the corresponding human sequence using an optimized CRISPR/Cas9-based protocol...
October 3, 2018: Zebrafish
Yue-Chuan Fu, Na Chen, Zi-Long Qiu, Lin Liu, Jie Shen
Retinitis pigmentosa (RP) is a common form of inherited retinal degeneration that causes progressive loss of vision or adult blindness, characterized by the impairment of rod and cone photoreceptors. At present, mutations in >60 pathogenic genes have been confirmed to cause RP. The predominant modes of inheritance are autosomal dominant, autosomal recessive and X‑linked. In addition, other modes of inheritance, including digenic or mitochondrial inheritance, have been reported. In previous decades, with the development of sequencing techniques, significant advances in identifying novel RP pathogenic genes and screening mutations have been made...
October 2, 2018: Molecular Medicine Reports
Ling Wan, Boling Deng, Zhengzheng Wu, Xiaoming Chen
Background: High myopia is a common ocular disease worldwide. To expand our current understanding of the genetic basis of high myopia, we carried out a whole exome sequencing (WES) study to identify potential causal gene mutations. Methods: A total of 20 individuals with high myopia were exome sequenced. A novel filtering strategy combining phenotypes and functional impact of variants was applied to identify candidate genes by multi-step bioinformatics analyses...
2018: PeerJ
Shanshan Han, Xiliang Liu, Shanglun Xie, Meng Gao, Fei Liu, Shanshan Yu, Peng Sun, Changquan Wang, Stephen Archacki, Zhaojing Lu, Xuebin Hu, Yayun Qin, Zhen Qu, Yuwen Huang, Yuexia Lv, Jiayi Tu, Jingzhen Li, Tinsae Assefa Yimer, Tao Jiang, Zhaohui Tang, Daji Luo, Fangyi Chen, Mugen Liu
Most cases of Usher syndrome type II (USH2) are due to mutations in the USH2A gene. There are no effective treatments or ideal animal models for this disease, and the pathological mechanisms of USH2 caused by USH2A mutations are still unknown. Here, we constructed a ush2a knockout (ush2a-/- ) zebrafish model using TALEN technology to investigate the molecular pathology of USH2. An early onset auditory disorder and abnormal morphology of inner ear stereocilia were identified in the ush2a-/- zebrafish. Consequently, the disruption of Ush2a in zebrafish led to a hearing impairment, like that in mammals...
October 2018: Human Genetics
María González-Del Pozo, Marta Martín-Sánchez, Nereida Bravo-Gil, Cristina Méndez-Vidal, Ángel Chimenea, Enrique Rodríguez-de la Rúa, Salud Borrego, Guillermo Antiñolo
Inherited Retinal Dystrophies are clinically and genetically heterogeneous disorders affecting the photoreceptors. Although NGS has shown to be helpful for the molecular diagnosis of these conditions, some cases remain unsolved. Among these, several individuals harboured monoallelic variants in a recessive gene, suggesting that a comprehensive screening could improve the overall diagnosis. In order to assess the contribution of non-coding variations in a cohort of 29 patients, 25 of them with monoallelic mutations, we performed targeted NGS...
September 6, 2018: Scientific Reports
Francisco Zurita-Díaz, María Del Carmen Ortuño-Costela, Ana Moreno-Izquierdo, Liliana Galbis, José María Millán, Carmen Ayuso, Rafael Garesse, M Esther Gallardo
A human iPSC line, IISHDOi004-A, from fibroblasts obtained from a patient with Usher syndrome, harboring a homozygous mutation in the USH2A gene (c.2276G>T; p.Cys759Phe) has been generated. Reprogramming factors Oct3/4, Sox2, Klf4, and c-Myc were delivered using Sendai virus.
August 2018: Stem Cell Research
Weijing Cai, Dapeng Zhou, Weibo Wu, Wen Ling Tan, Jiaqian Wang, Caicun Zhou, Yanyan Lou
BACKGROUND: Mutant peptides presented by MHC (major histocompatibility complex) Class II in cancer are important targets for cancer immunotherapy. Both animal studies and clinical trials in cancer patients showed that CD4 T cells specific to tumor-derived mutant peptides are essential for the efficacy of immune checkpoint blockade therapy by PD1 antibody. RESULTS: In this study, we analyzed the next generation sequencing data of 147 lung adenocarcinoma patients from The Cancer Genome Atlas and predicted neoantigens presented by MHC Class I and Class II molecules...
August 3, 2018: BMC Genomics
Iikki Donner, Riku Katainen, Lauri J Sipilä, Mervi Aavikko, Eero Pukkala, Lauri A Aaltonen
OBJECTIVES: Although the primary cause of lung cancer is smoking, a considerable proportion of all lung cancers occur in never smokers. Gender influences the risk and characteristics of lung cancer and women are overrepresented among never smokers with the disease. Young age at onset and lack of established environmental risk factors suggest genetic predisposition. In this study, we used population-based sampling of young patients to discover candidate predisposition variants for lung adenocarcinoma in never-smoking women...
August 2018: Lung Cancer: Journal of the International Association for the Study of Lung Cancer
Rubén Cabanillas, Marta Diñeiro, Guadalupe A Cifuentes, David Castillo, Patricia C Pruneda, Rebeca Álvarez, Noelia Sánchez-Durán, Raquel Capín, Ana Plasencia, Mónica Viejo-Díaz, Noelia García-González, Inés Hernando, José L Llorente, Alfredo Repáraz-Andrade, Cristina Torreira-Banzas, Jordi Rosell, Nancy Govea, Justo Ramón Gómez-Martínez, Faustino Núñez-Batalla, José A Garrote, Ángel Mazón-Gutiérrez, María Costales, María Isidoro-García, Belén García-Berrocal, Gonzalo R Ordóñez, Juan Cadiñanos
BACKGROUND: Sensorineural hearing loss (SNHL) is the most common sensory impairment. Comprehensive next-generation sequencing (NGS) has become the standard for the etiological diagnosis of early-onset SNHL. However, accurate selection of target genomic regions (gene panel/exome/genome), analytical performance and variant interpretation remain relevant difficulties for its clinical implementation. METHODS: We developed a novel NGS panel with 199 genes associated with non-syndromic and/or syndromic SNHL...
July 9, 2018: BMC Medical Genomics
Giacomo Calzetti, Richard A Levy, Artur V Cideciyan, Alexandra V Garafalo, Alejandro J Roman, Alexander Sumaroka, Jason Charng, Elise Heon, Samuel G Jacobson
PURPOSE: To determine the change in vision and retinal structure in patients with the common c.2299delG mutation in the USH2A gene in anticipation of clinical trials of therapy. DESIGN: Retrospective observational case series. METHODS: Eighteen patients, homozygotes or compound heterozygotes with the c.2299delG mutation in USH2A, were studied with regard to visual acuity, kinetic perimetry, dark- and light-adapted static perimetry, optical coherence tomography (OCT), and autofluorescence (AF) imaging...
September 2018: American Journal of Ophthalmology
Ludmila Pawlikowska, Jeffrey Nelson, Diana E Guo, Charles E McCulloch, Michael T Lawton, Helen Kim, Marie E Faughnan
BACKGROUND: Hereditary hemorrhagic telangiectasia (HHT) is caused by mutations in TGFβ/BMP9 pathway genes and characterized by vascular malformations (VM) including arteriovenous malformations (AVM) in lung, liver, and brain, which lead to severe complications including intracranial hemorrhage (ICH) from brain VM. The clinical heterogeneity of HHT suggests a role for genetic modifier effects. Common variants in loci that modify phenotype severity in Tgfb knockout mice were previously reported as associated with lung AVM in HHT...
May 2018: Molecular Genetics & Genomic Medicine
B Xu, Y Chen, A Jiang, C Chen, K Wang, J Zheng, Y Fu
Objective: The next-generation sequencing technology (NGS) was used to perform genetic testing on children diagnosed with sensorineural hearing loss in outpatient clinics.The information on the status and inheritance of disease causing genes in deafness was analyzed to provide a theoretical basis for genetic counseling, prenatal diagnosis, and birth defects prevention. Method: Ninety-four cases of sensorineural deafness diagnosed by medical history, audiological examination, and imaging examination were collected in our department...
June 5, 2018: Journal of Clinical Otorhinolaryngology, Head, and Neck Surgery
Raquel Pérez-Carro, Fiona Blanco-Kelly, Lilián Galbis-Martínez, Gema García-García, Elena Aller, Blanca García-Sandoval, Pablo Mínguez, Marta Corton, Ignacio Mahíllo-Fernández, Inmaculada Martín-Mérida, Almudena Avila-Fernández, José M Millán, Carmen Ayuso
INTRODUCTION: Mutations in USH2A cause both isolated Retinitis Pigmentosa (RP) and Usher syndrome (that implies RP and hearing impairment). One of the most frequent variants identified in this gene and among these patients is the p.(Cys759Phe) change. However, the pathogenic role of this allele has been questioned since it was found in homozygosity in two healthy siblings of a Spanish family. To assess the causative role of USH2A p.(Cys759Phe) in autosomal recessive RP (ARRP) and Usher syndrome type II (USH2) and to establish possible genotype-phenotype correlations associated with p...
2018: PloS One
Lulin Huang, Yao Mao, Jiyun Yang, Yuanfeng Li, Yang Li, Zhenglin Yang
OBJECTIVES: USH2A encodes for usherin, a basement membrane protein in the inner ear and retina. USH2A can cause retinitis pigmentosa (RP) with or without hearing loss. The aim of this study was to detect USH2A mutations in a Chinese cohort of 75 small RP families and 10 Usher syndrome families. METHODS: We performed a direct Sanger sequencing analysis of the USH2A gene to identify mutations for this cohort. RESULTS: We identified a total of eight mutations in four of the 75 small RP families (5...
June 13, 2018: Eye
Margo Dona, Ralph Slijkerman, Kimberly Lerner, Sanne Broekman, Jeremy Wegner, Taylor Howat, Theo Peters, Lisette Hetterschijt, Nanda Boon, Erik de Vrieze, Nasrin Sorusch, Uwe Wolfrum, Hannie Kremer, Stephan Neuhauss, Jingjing Zang, Maarten Kamermans, Monte Westerfield, Jennifer Phillips, Erwin van Wijk
Mutations in USH2A are the most frequent cause of Usher syndrome and autosomal recessive nonsyndromic retinitis pigmentosa. To unravel the pathogenic mechanisms underlying USH2A-associated retinal degeneration and to evaluate future therapeutic strategies that could potentially halt the progression of this devastating disorder, an animal model is needed. The available Ush2a knock-out mouse model does not mimic the human phenotype, because it presents with only a mild and late-onset retinal degeneration. Using CRISPR/Cas9-technology, we introduced protein-truncating germline lesions into the zebrafish ush2a gene (ush2armc1 : c...
August 2018: Experimental Eye Research
Yujia Yang, Xiaozhu Wang, Yang Liu, Qiang Fu, Changxu Tian, Chenglong Wu, Huitong Shi, Zihao Yuan, Suxu Tan, Shikai Liu, Dongya Gao, Rex Dunham, Zhanjiang Liu
In aquatic organisms, hearing is an important sense for acoustic communications and detection of sound-emitting predators and prey. Channel catfish is a dominant aquaculture species in the United States. As channel catfish can hear sounds of relatively high frequency, it serves as a good model for study auditory mechanisms. In catfishes, Weberian ossicles connect the swimbladder to the inner ear to transfer the forced vibrations and improve hearing ability. In this study, we examined the transcriptional profiles of channel catfish swimbladder and other four tissues (gill, liver, skin, and intestine)...
September 2018: Comparative Biochemistry and Physiology. Part D, Genomics & Proteomics
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