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Targeted Exome Sequencing Identified Novel USH2A Mutations in Usher Syndrome Families  [PDF]
Xiu-Feng Huang, Ping Xiang, Jie Chen, Dong-Jun Xing, Na Huang, Qingjie Min, Feng Gu, Yi Tong, Chi-Pui Pang, Jia Qu, Zi-Bing Jin
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0063832
Abstract: Usher syndrome (USH) is a leading cause of deaf-blindness in autosomal recessive trait. Phenotypic and genetic heterogeneities in USH make molecular diagnosis much difficult. This is a pilot study aiming to develop an approach based on next-generation sequencing to determine the genetic defects in patients with USH or allied diseases precisely and effectively. Eight affected patients and twelve unaffected relatives from five unrelated Chinese USH families, including 2 pseudo-dominant ones, were recruited. A total of 144 known genes of inherited retinal diseases were selected for deep exome resequencing. Through systematic data analysis using established bioinformatics pipeline and segregation analysis, a number of genetic variants were released. Eleven mutations, eight of them were novel, in the USH2A gene were identified. Biparental mutations in USH2A were revealed in 2 families with pseudo-dominant inheritance. A proband was found to have triple mutations, two of them were supposed to locate in the same chromosome. In conclusion, this study revealed the genetic defects in the USH2A gene and demonstrated the robustness of targeted exome sequencing to precisely and rapidly determine genetic defects. The methodology provides a reliable strategy for routine gene diagnosis of USH.
Analysis of the Ush2a Gene in Medaka Fish (Oryzias latipes)  [PDF]
Elena Aller, Ana V. Sánchez-Sánchez, Javier U. Chicote, Gema García-García, Patricia Udaondo, Laura Cavallé, Marina Piquer-Gil, Antonio García-Espa?a, Manuel Díaz-Llopis, José M. Millán, José L. Mullor
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0074995
Abstract: Patients suffering from Usher syndrome (USH) exhibit sensorineural hearing loss, retinitis pigmentosa (RP) and, in some cases, vestibular dysfunction. USH is the most common genetic disorder affecting hearing and vision and is included in a group of hereditary pathologies associated with defects in ciliary function known as ciliopathies. This syndrome is clinically classified into three types: USH1, USH2 and USH3. USH2 accounts for well over one-half of all Usher cases and mutations in the USH2A gene are responsible for the majority of USH2 cases, but also for atypical Usher syndrome and recessive non-syndromic RP. Because medaka fish (Oryzias latypes) is an attractive model organism for genetic-based studies in biomedical research, we investigated the expression and function of the USH2A ortholog in this teleost species. Ol-Ush2a encodes a protein of 5.445 aa codons, containing the same motif arrangement as the human USH2A. Ol-Ush2a is expressed during early stages of medaka fish development and persists into adulthood. Temporal Ol-Ush2a expression analysis using whole mount in situ hybridization (WMISH) on embryos at different embryonic stages showed restricted expression to otoliths and retina, suggesting that Ol-Ush2a might play a conserved role in the development and/or maintenance of retinal photoreceptors and cochlear hair cells. Knockdown of Ol-Ush2a in medaka fish caused embryonic developmental defects (small eyes and heads, otolith malformations and shortened bodies with curved tails) resulting in late embryo lethality. These embryonic defects, observed in our study and in other ciliary disorders, are associated with defective cell movement specifically implicated in left-right (LR) axis determination and planar cell polarity (PCP).
An Update on the Genetics of Usher Syndrome  [PDF]
José M. Millán,Elena Aller,Teresa Jaijo,Fiona Blanco-Kelly,Ascensión Gimenez-Pardo,Carmen Ayuso
Journal of Ophthalmology , 2011, DOI: 10.1155/2011/417217
Abstract: Usher syndrome (USH) is an autosomal recessive disease characterized by hearing loss, retinitis pigmentosa (RP), and, in some cases, vestibular dysfunction. It is clinically and genetically heterogeneous and is the most common cause underlying deafness and blindness of genetic origin. Clinically, USH is divided into three types. Usher type I (USH1) is the most severe form and is characterized by severe to profound congenital deafness, vestibular areflexia, and prepubertal onset of progressive RP. Type II (USH2) displays moderate to severe hearing loss, absence of vestibular dysfunction, and later onset of retinal degeneration. Type III (USH3) shows progressive postlingual hearing loss, variable onset of RP, and variable vestibular response. To date, five USH1 genes have been identified: MYO7A (USH1B), CDH23 (USH1D), PCDH15 (USH1F), USH1C(USH1C), and USH1G(USH1G). Three genes are involved in USH2, namely, USH2A (USH2A), GPR98 (USH2C), and DFNB31 (USH2D). USH3 is rare except in certain populations, and the gene responsible for this type is USH3A.
Mutational screening of the USH2A gene in Spanish USH patients reveals 23 novel pathogenic mutations
Gema Garcia-Garcia, Maria J Aparisi, Teresa Jaijo, Regina Rodrigo, Ana M Leon, Almudena Avila-Fernandez, Fiona Blanco-Kelly, Sara Bernal, Rafael Navarro, Manuel Diaz-Llopis, Montserrat Baiget, Carmen Ayuso, Jose M Millan, Elena Aller
Orphanet Journal of Rare Diseases , 2011, DOI: 10.1186/1750-1172-6-65
Abstract: To identify the genetic cause of the disease and determine the frequency of USH2A mutations in a cohort of 88 unrelated USH Spanish patients, we carried out a mutation screening of the 72 coding exons of this gene by direct sequencing. Moreover, we performed functional minigene studies for those changes that were predicted to affect splicing.As a result, a total of 144 DNA sequence variants were identified. Based upon previous studies, allele frequencies, segregation analysis, bioinformatics' predictions and in vitro experiments, 37 variants (23 of them novel) were classified as pathogenic mutations.This report provide a wide spectrum of USH2A mutations and clinical features, including atypical Usher syndrome phenotypes resembling Usher syndrome type I. Considering only the patients clearly diagnosed with Usher syndrome type II, and results obtained in this and previous studies, we can state that mutations in USH2A are responsible for 76.1% of USH2 disease in patients of Spanish origin.Usher syndrome (USH) is an autosomal recessive disease characterized by hearing loss, retinitis pigmentosa (RP), and, in some cases, vestibular dysfunction. It is clinically and genetically heterogeneous and is the most common cause underlying deafness and blindness of genetic origin. Clinically, USH is divided into three types. Usher type I (USH1) is the most severe form and is characterized by severe to profound congenital deafness, vestibular areflexia, and prepubertal onset of progressive RP. Type II (USH2) displays moderate to severe hearing loss, absence of vestibular dysfunction, and later onset of retinal degeneration. Type III (USH3) shows progressive postlingual hearing loss, variable onset of RP, and variable vestibular response. To date, five USH1 genes have been identified: MYO7A (USH1B), CDH23 (USH1D), PCDH15 (USH1F), USH1C(USH1C), and USH1G(USH1G). Three genes are involved in USH2, namely, USH2A (USH2A), GPR98 (USH2C), and DFNB31 (USH2D). USH3 is rare except in certain
An Update on the Genetics of Usher Syndrome  [PDF]
José M. Millán,Elena Aller,Teresa Jaijo,Fiona Blanco-Kelly,Ascensión Gimenez-Pardo,Carmen Ayuso
Journal of Ophthalmology , 2011, DOI: 10.1155/2011/417217
Abstract: Usher syndrome (USH) is an autosomal recessive disease characterized by hearing loss, retinitis pigmentosa (RP), and, in some cases, vestibular dysfunction. It is clinically and genetically heterogeneous and is the most common cause underlying deafness and blindness of genetic origin. Clinically, USH is divided into three types. Usher type I (USH1) is the most severe form and is characterized by severe to profound congenital deafness, vestibular areflexia, and prepubertal onset of progressive RP. Type II (USH2) displays moderate to severe hearing loss, absence of vestibular dysfunction, and later onset of retinal degeneration. Type III (USH3) shows progressive postlingual hearing loss, variable onset of RP, and variable vestibular response. To date, five USH1 genes have been identified: MYO7A (USH1B), CDH23 (USH1D), PCDH15 (USH1F), USH1C(USH1C), and USH1G(USH1G). Three genes are involved in USH2, namely, USH2A (USH2A), GPR98 (USH2C), and DFNB31 (USH2D). USH3 is rare except in certain populations, and the gene responsible for this type is USH3A. 1. Introduction Usher syndrome (USH) was first described by von Graefe in 1858 and is characterized by the association of sensorineural hearing loss, retinitis pigmentosa (RP), and, in some cases, vestibular dysfunction. Its heritability was established by Charles Usher, a British ophthalmologist [1]. The syndrome is inherited in an autosomal recessive pattern. The syndrome is the most frequent cause of deaf-blindness, accounting for more than 50% of individuals who are both deaf and blind [2, 3], about 18% of RP cases [4], and 5% of all cases of congenital deafness [5]. Its range of prevalence is 3.2–6.2/100,000 depending on the study [2, 4, 6–8]. Usher patients present progressive photoreceptor degeneration in the retina called retinitis pigmentosa, which leads to a loss of peripheral vision. This degeneration is predominantly attributable to rod dysfunction, although cones usually degenerate later in the course of the disease. Clinical symptoms may vary and include night blindness (nyctalopia) with elevated dark adaptation thresholds, abnormal electroretinogram responses, visual field constriction, abnormal retinal pigmentation including peripheral bone spicules, arterial narrowing, and optic-nerve pallor, and predisposition to myopia and posterior subcapsular cataracts [9]. The human inner ear consists of the cochlea, a snail-shaped organ which mediates sound transduction, and the vestibular labyrinth, which detects gravitational force and angular and linear accelerations. Both structures have specialized
Genetic Analysis for Two Italian Siblings with Usher Syndrome and Schizophrenia  [PDF]
Daniela Domanico,Serena Fragiotta,Paolo Trabucco,Marcella Nebbioso,Enzo Maria Vingolo
Case Reports in Ophthalmological Medicine , 2012, DOI: 10.1155/2012/380863
Abstract: Usher syndrome is a group of autosomal recessive genetic disorders characterized by deafness, retinitis pigmentosa, and sometimes vestibular areflexia. The relationship between Usher syndrome and mental disorders, most commonly a “schizophrenia-like” psychosis, is sometimes described in the literature. The etiology of psychiatric expression of Usher syndrome is still unclear. We reported a case of two natural siblings with congenital hypoacusis, retinitis pigmentosa, and psychiatric symptoms. Clinical features and genetic analysis were also reported. We analyzed possible causes to explain the high prevalence of psychiatric manifestations in Usher syndrome: genetic factors, brain damage, and “stress-related” hypothesis. 1. Introduction Usher syndrome represents a group of clinically variable and genetically heterogeneous disorders characterized by congenital sensorineural hearing loss, retinitis pigmentosa (RP), and sometimes vestibular areflexia [1]. Three clinical subtypes of Usher syndrome were recognized. Type I (USH1) is characterized by profound congenital deafness, prepubertal-onset retinitis pigmentosa, and vestibular dysfunction. Usher syndrome type II (USH2) is characterized by congenital mild to severe hearing loss, adolescent-onset retinitis pigmentosa, and no vestibular dysfunction. Usher syndrome type III (USH3) is characterized by rapidly progressive hearing loss. Age of onset of retinitis pigmentosa and degree of vestibular dysfunction are variable [2, 3]. To date, seven loci (USH1B-USH1H) and five genes for USH1 have been reported: USH1C, MYO7A, CDH23, PCDH15, and USH1G. Three genetic loci (USH2A, USH2C, and USH2D) and three genes (USH2A, GPR98, and DFNB31) have been identified in USH2. Mutations in USH2A gene on chromosome 1q41 are the most common mutations (85% of all cases with USH2). USH3 is caused by mutations in USH3A (clarin-1) gene, mapped on 3q21-q25 [4, 5]. Previous studies reported association between Usher syndrome and mental disorders, most commonly schizophrenia. Although Hallgren reported a prevalence of about 23% of psychotic disorders in individuals with Usher syndrome, other authors reported a prevalence of schizophrenia of only 4.5% [6, 7]. In addition, Dammeyer reported that 23% of individuals with Usher syndrome were affected by mental and behavioral disorders (such as mental retardation, anorexia nervosa, and ADHD) [8]. Case 1. A 26-year-old Caucasian female, born through an eutocic uncomplicated delivery, was first admitted to our department at the age of 23 complaining of gradual vision loss and hemeralopia in the
An overview of oculocutaneous albinism: report of TYR gene mutations in five Colombian individuals Una mirada al albinismo oculocutáneo: reporte de mutaciones en el gen TYR en cinco individuos colombianos  [cached]
Diana Sanabria,Helena Groot,Julio Guzmán,María Claudia Lattig
Biomédica , 2011,
Abstract: Introduction. Oculocutaneus albinism is a pigment-related inherited disorder characterized by hypopigmentation of the skin, hair and eyes, foveal hypoplasia and low vision. To date, 230 mutations in the TYR gene have been reported as responsible for oculocutaneus albinism type 1 worldwide. TYR gene encodes the enzyme tyrosinase involved in the metabolic pathway of melanin synthesis. Objectives. Identify mutations in the TYR gene responsible for oculocutaneous albinism type 1 in five Colombian individuals; four of them belong to a single family and the fifth one is an isolated case not related to the family. Test a newfangled ophthalmic system to correct refraction defects, decrease nystagmus movements and photophobia in a patient with oculocutaneous albinism in one of the patients. Materials and methods. Sequencing of the five exons in the TYR gene and search for possible carriers in the family. Clinical ophthalmological evaluation and implementation of an oculo-visual system. Results. We identified the G47D and 1379delTT mutation in the family, the isolated case was a compound heterozygote for the G47D and D42N mutations. The oculo-visual corrective system was able to increase visual acuity and to diminish the nystagmus. Conclusions. This is the first study in Colombia where albinism mutations are reported enabling future molecular screening studies in our Colombian population. Introducción. El albinismo oculocutáneo es un desorden hereditario autosómico recesivo relacionado con la pigmentación. Sus manifestaciones clínicas incluyen hipopigmentación en piel, cabello y ojos, hipoplasia en la fóvea y baja visión. A nivel mundial, hasta el momento, han sido reportadas aproximadamente 230 mutaciones en el gen TYR que causan albinismo oculocutáneo tipo 1. Este gen codifica para la tirosinasa, enzima principal de la biosíntesis de melanina. Objetivos. Identificar mutaciones en el gen TYR responsables del albinismo oculocutáneo tipo 1 en cinco individuos colombianos; cuatro de ellos pertenecen a una misma familia y el otro individuo es un caso aislado no relacionado con la familia. Asimismo, se pretende evaluar un sistema oftálmico que permite corregir problemas de refracción, disminuir el nystagmus y la fotofobia en uno de los casos. Materiales y métodos. Secuenciación de los cinco exones del gen TYR en los cinco individuos de estudio y búsqueda de portadores en la familia. Evaluación clínica oftalmológica e implementación del sistema correctivo. Resultados. Se encontraron las mutaciones G47D y 1379 del TT en la familia; en el individuo aislado se encontró q
Aspectos genéticos y clínicos del síndrome de usher Genetical and clinical aspects of Usher syndrome
Beatriz Dyce Gordon,Josefina Mejías Márquez,Mirtha Copello Noblet,Raisa Hernández Baguer
Revista Cubana de Oftalmolog?-a , 2000,
Abstract: Con el objetivo de describir algunos aspectos genéticos y clínicos del Síndrome de Usher, se realizó un estudio descriptivo transversal en el Centro de Referencia Nacional de Retinosis Pigmentaria desde marzo de 1996 hasta junio de 1998, con 33 pacientes con diagnóstico de síndrome de Usher a través de la revisión de historias clínicas, entrevistas para interrogatorio y examen físico, así como para la confección e interpretación del árbol genealógico. La mayoría de los pacientes (60,60 %) presentaron el síndrome de Usher tipo II. Se encontró consanguinidad en el 29,62 % de los casos y los antecedentes patológicos familiares se observaron en 12 familias. Las manifestaciones clínicas oftalmológicas tuvieron un inicio fundamentalmente juvenil, y las audiológicas tuvieron un inicio muy precoz (congénito) en el tipo I y en la infancia, en el tipo II. En conclusión en el presente estudio, se pone de manifiesto la heterogeneidad clínica y genética del síndrome de Usher así como su carácter hereditario con patrón de herencia autosómico recesivo. Se hace necesario su diagnóstico precoz para ofrecer asesoramiento genético a los padres y poner tratamiento adecuado a las discapacidades With the aim of describe some genetic and clinical features of Usher′s syndrome, we performed a cross and descriptive study in National Center of Remission of Pigmentosa Retinitis from March 1996 o June 1998, where 33 patients were diagnosed of Usher′s syndrome through revision of medical records, interviews for interrogation and physical examination, as well as to drawing up and interpretation of genealogical tree. Most patients (60,60 %) presenting with type II Usher′s syndrome. We found consanguinity in 29,62 % of cases and familial pathologic bacgrounds were observed in 12 families. Ophthalmologic and clinical manifestations had a youthful onset, and audiologies had a very early onset (congenital) in type I, and in infancy in type II. In conclusion, in present study was evident clinical and genetic heterogeneity of Usher′s syndrome as well as hereditary character with a autosomal recessive pattern of inheritance. It is necessary its early diagnosis to offer genetical advising to parents and to treat disabilities
The mitotic spindle protein SPAG5/Astrin connects to the Usher protein network postmitotically
Ferry FJ Kersten, Erwin van Wijk, Lisette Hetterschijt, Katharina Bauβ, Theo A Peters, Mariam G Aslanyan, Bert van der Zwaag, Uwe Wolfrum, Jan EE Keunen, Ronald Roepman, Hannie Kremer
Cilia , 2012, DOI: 10.1186/2046-2530-1-2
Abstract: We identified the centrosomal and microtubule-associated protein sperm-associated antigen (SPAG)5 in the retina. SPAG5 was also found to interact with another previously described USH2AisoB interaction partner: the centrosomal ninein-like protein NINLisoB. Using In situ hybridization, we found that Spag5 was widely expressed during murine embryonic development, with prominent signals in the eye, cochlea, brain, kidney and liver. SPAG5 expression in adult human tissues was detected by quantitative PCR, which identified expression in the retina, brain, intestine, kidney and testis. In the retina, Spag5, Ush2aisoB and NinlisoB were present at several subcellular structures of photoreceptor cells, and colocalized at the basal bodies.Based on these results and on the suggested roles for USH proteins in vesicle transport and providing structural support to both the inner ear and the retina, we hypothesize that SPAG5, USH2AisoB and NINLisoB may function together in microtubule-based cytoplasmic trafficking of proteins that are essential for cilium formation, maintenance and/or function.Mutations in the gene for Usher syndrome 2A (USH2A) are causative for non-syndromic recessive retinitis pigmentosa (RP) [1-4] and for Usher syndrome type II (USH2), a recessive disease characterized by congenital moderate to severe stable hearing loss, and RP that often leads to blindness [5]. Mutations in this gene probably account for 8 to 20% of the autosomal recessive RP cases [3,6], and are suggested to be the commonest cause of RP in the USA [3]. It is estimated that up to 85% of patients with USH2 and about half of all patients with Usher syndrome have mutations in USH2A [7]. All proteins encoded by genes associated with USH1 and USH2 are present in hair cells and photoreceptor cells, and are interconnected in a network of interacting proteins [8-12].To gain insight into the molecular pathology of retinal degeneration resulting from USH2A mutations, we aimed to determine the retinal r
Gothicism in The Fall of the House of Usher  [PDF]
Wenfang Pang, Diqiu Wang, Shanshan Hu
Advances in Literary Study (ALS) , 2015, DOI: 10.4236/als.2015.31003
Abstract: Edgar Allan Poe is one of the most unique writers in America. He stands alone with his aesthetic taste and writing principle, engaged in the morbid theme of nightmare, death, crime and evil. Consequently, he adopts Gothic technique in a composition, taking a full advantage of Gothic subject matter, plot and elements and lingering on violence, murder, insanity and collapse. The Fall of the House of Usher is Poe’s classical piece of this type. It presents terrifying atmosphere, the dark plot, and man’s psychological terror to reveal the process of disintegration and annihilation of human mind, thus offering readers specific aesthetic perception through psychological shocks. This paper borrowing a critical perspective of Gothic tradition and theory of the sublime, tries to analyze the Gothicism in this novel to detect its aesthetic feature.
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