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1.
Hum Mutat ; 41(1): 140-149, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31456290

RESUMO

Inherited retinal diseases (IRDs) cause visual loss due to dysfunction or progressive degeneration of photoreceptors. These diseases show marked phenotypic and genetic heterogeneity. The Israeli IRD consortium (IIRDC) was established in 2013 with the goal of performing clinical and genetic mapping of the majority of Israeli IRD patients. To date, we recruited 2,420 families including 3,413 individuals with IRDs. On the basis of our estimation, these patients represent approximately 40% of Israeli IRD patients. To the best of our knowledge, this is, by far, the largest reported IRD cohort, and one of the first studies addressing the genetic analysis of IRD patients on a nationwide scale. The most common inheritance pattern in our cohort is autosomal recessive (60% of families). The most common retinal phenotype is retinitis pigmentosa (43%), followed by Stargardt disease and cone/cone-rod dystrophy. We identified the cause of disease in 56% of the families. Overall, 605 distinct mutations were identified, of which 12% represent prevalent founder mutations. The most frequently mutated genes were ABCA4, USH2A, FAM161A, CNGA3, and EYS. The results of this study have important implications for molecular diagnosis, genetic screening, and counseling, as well as for the development of new therapeutic strategies for retinal diseases.


Assuntos
Doenças Genéticas Inatas/epidemiologia , Doenças Genéticas Inatas/genética , Predisposição Genética para Doença , Doenças Retinianas/epidemiologia , Doenças Retinianas/genética , Alelos , Substituição de Aminoácidos , Análise Mutacional de DNA , Eletrorretinografia , Efeito Fundador , Estudos de Associação Genética , Doenças Genéticas Inatas/diagnóstico , Testes Genéticos , Geografia Médica , Humanos , Padrões de Herança , Israel/epidemiologia , Mutação , Vigilância da População , Doenças Retinianas/diagnóstico , Sequenciamento Completo do Genoma
2.
Am J Hum Genet ; 86(5): 783-8, 2010 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-20398884

RESUMO

With a worldwide prevalence of 1 in 4,000, retinitis pigmentosa (RP) is the most common form of hereditary retinal degeneration. More than 30 genes and loci have been implicated in nonsyndromic autosomal-recessive (ar) RP. Genome-wide homozygosity mapping was conducted in one Dutch and one Israeli family affected by arRP. The families were found to share a 5.9 Mb homozygous region on chromosome 2p23.1-p23.3. A missense variant in one of the genes residing in this interval, C2ORF71, has recently been reported to be associated with RP. C2ORF71, encoding a putative protein of 1,288 amino acids, was found to be specifically expressed in human retina. Furthermore, RT-PCR analysis revealed that in the mouse eye, C2orf71 is expressed as early as embryonic day 14. Mutation analysis detected a 1 bp deletion (c.946 del; p.Asn237MetfsX5) segregating with RP in the Dutch family, whereas a nonsense mutation (c.556C > T; p.Gln186X) was identified in the Israeli family. Microsatellite-marker analysis in additional Israeli families revealed cosegregation of a C2ORF71-linked haplotype in one other family, in which a 13 bp deletion (c.2756_2768 del; p.Lys919ThrfsX) was identified. Clinically, patients with mutations in C2ORF71 show signs of typical RP; these signs include poor night vision and peripheral field loss, typical retinal bone-spicule-type pigment deposits, pale appearance of the optic disk, and markedly reduced or completely extinguished electroretinograms. In conclusion, truncating mutations in C2ORF71 were identified in three unrelated families, thereby confirming the involvement of this gene in the etiology of arRP.


Assuntos
Mutação , Proteínas/genética , Retina/metabolismo , Retinose Pigmentar/genética , Animais , Mapeamento Cromossômico , Análise Mutacional de DNA , Proteínas do Olho/genética , Haplótipos , Homozigoto , Humanos , Camundongos , Repetições de Microssatélites , Mutação de Sentido Incorreto , Reação em Cadeia da Polimerase Via Transcriptase Reversa
3.
Am J Med Genet A ; 149A(4): 650-6, 2009 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-19140180

RESUMO

Retinitis pigmentosa is the most common form of hereditary retinal degeneration, with a worldwide prevalence of 1 in 4,000. At least 28 genes and loci have been implicated in nonsyndromic autosomal recessive retinitis pigmentosa. Here we report two extended and highly consanguineous families segregating early onset retinitis pigmentosa. Despite the consanguinity in both families, we found allelic heterogeneity in one of them, in which affected individuals were compound heterozygotes for two different mutations of the CRB1 gene. In the second family we found evidence for locus heterogeneity. A novel homozygous mutation of RDH12 was found in only 14 of 17 affected individuals in this family. Our data indicate that in the other affected individuals the disease is caused by a different gene/s. These findings demonstrate that while homozygosity mapping is an efficient tool for identification of the underlying mutated genes in inbred families, both locus and allelic heterogeneity may occur even within the same consanguineous family. These observations should be taken into account, especially when studying common and heterogeneous recessive genetic conditions.


Assuntos
Degeneração Retiniana/genética , Adolescente , Adulto , Idade de Início , Oxirredutases do Álcool/genética , Alelos , Sequência de Aminoácidos , Árabes/genética , Sequência de Bases , Criança , Pré-Escolar , Mapeamento Cromossômico , Consanguinidade , Análise Mutacional de DNA , Primers do DNA/genética , Proteínas do Olho/genética , Feminino , Genes Recessivos , Haplótipos , Heterozigoto , Homozigoto , Humanos , Lactente , Israel , Masculino , Proteínas de Membrana/genética , Pessoa de Meia-Idade , Dados de Sequência Molecular , Proteínas do Tecido Nervoso/genética , Linhagem , Fenótipo , Homologia de Sequência de Aminoácidos
4.
Harefuah ; 148(2): 125-9, 138, 2009 Feb.
Artigo em Hebraico | MEDLINE | ID: mdl-19627043

RESUMO

In this article the authors review the history of ophthalmology in the Holy Land in the era spanning from 1948 till nowadays. Although there is material concerning ophthalmology in the Holy Land, it is not well organized. Therefore, the authors considered it of utmost importance to gather all the material that exists regarding ophthalmology in the Holy Land. In this review the authors strived to present a view of ophthalmology in the Holy Land in its first steps. Moreover, the authors presented the latest developments in eye health care in local eye departments.


Assuntos
Oftalmologia/história , História do Século XX , História do Século XXI , Israel , Oriente Médio
5.
Mol Vis ; 14: 675-82, 2008 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-18432314

RESUMO

PURPOSE: To investigate the genetic basis for autosomal recessive severe early-onset retinitis pigmentosa (RP) in a consanguineous Israeli Muslim Arab family. METHODS: Haplotype analysis for all known genes underlying autosomal recessive RP was performed. Mutation screening of the underlying gene was done by direct sequencing. An in vitro splicing assay was used to evaluate the effect of the identified mutation on splicing. RESULTS: Haplotype analysis indicated linkage to the Tubby-like protein 1 (TULP)1 gene. Direct sequencing revealed a homozygous single base insertion, c.1495+2_1495+3insT, located in the conserved donor splice-site of intron 14. This mutation co-segregated with the disease, and was not detected in 114 unrelated Israeli Muslim Arab controls. We used an in vitro splicing assay to demonstrate that this mutation leads to incorrect splicing. CONCLUSIONS: To date, 22 distinct pathogenic mutations of TULP1 have been reported in patients with early-onset RP or Leber congenital amaurosis. Here we report a novel splice-site mutation of TULP1, c.1495+2_1495+3insT, underlying autosomal recessive early-onset RP in a consanguineous Israeli Muslim Arab family. This report expands the spectrum of pathogenic mutations of the TULP1 gene.


Assuntos
Árabes/genética , Proteínas do Olho/genética , Islamismo , Mutação/genética , Sítios de Splice de RNA/genética , Retinose Pigmentar/epidemiologia , Retinose Pigmentar/genética , Adulto , Idade de Início , Idoso , Sequência de Bases , Consanguinidade , Análise Mutacional de DNA , Éxons/genética , Família , Feminino , Fundo de Olho , Haplótipos , Humanos , Íntrons/genética , Israel/epidemiologia , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Linhagem
6.
Harefuah ; 147(6): 547-52, 572, 2008 Jun.
Artigo em Hebraico | MEDLINE | ID: mdl-18693634

RESUMO

This article reviews the history of ophthalmology in the Middle East in the era spanning from antiquity to the twentieth century. Although there is little material concerning ophthalmology in antiquity the authors strove to present the way people and healers overcome eye problems. Moreover, ophthalmology in middle ages was reviewed, with emphasis on the great role Arab and Muslim ophthalmologists had in developing eye care and ocular sciences. Finally, the latest developments in eye health care in our region were shown.


Assuntos
Oftalmologia/história , Oftalmopatias/história , Oftalmopatias/terapia , História do Século XX , História Antiga , História Medieval , Humanos , Oriente Médio , Oftalmologia/tendências
7.
Invest Ophthalmol Vis Sci ; 48(12): 5431-8, 2007 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-18055789

RESUMO

PURPOSE: To investigate the genetic basis and clinical manifestations of a characteristic form of retinal degeneration in the Yemenite Jewish population. METHODS: Haplotype analysis for all known genes and loci underlying autosomal recessive nonsyndromic retinal degeneration was performed in a Yemenite Jewish family segregating autosomal recessive severe retinal degeneration. The causative mutation was detected by direct sequencing of the underlying gene, and its prevalence in additional affected and unaffected Yemenite Jews was determined. Patients who were homozygous for this mutation underwent ophthalmic evaluation, including funduscopy, electroretinography, electro-oculography, perimetry, and color vision testing. RESULTS: In the studied Yemenite Jewish family, we found evidence for linkage to the CERKL gene. Direct sequencing revealed a novel homozygous splice-site mutation, c.238+1G>A. An in vitro splicing assay demonstrated that this mutation leads to incorrect splicing. c.238+1G>A was found to cause retinal degeneration in six additional Yemenite Jewish families. The carrier frequency of this mutation in the Yemenite Jewish population is 4.4%. All c.238+1G>A homozygotes manifest widespread progressive impairment of rod and cone function with early macular involvement. CONCLUSIONS: c.238+1G>A is the second reported mutation of CERKL and is a prevalent founder mutation that underlies approximately 33% of autosomal recessive retinal degeneration cases in the Yemenite Jewish population. It is associated with a characteristic retinal degeneration phenotype with early macular involvement, concomitant progression of rod and cone impairment, and characteristic fundus findings. The identification of this mutation and phenotype will facilitate molecular diagnosis, carrier screening, and genetic counseling in the Yemenite Jewish population.


Assuntos
Efeito Fundador , Judeus/genética , Macula Lutea/patologia , Mutação/genética , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Degeneração Retiniana/genética , Adolescente , Adulto , Testes de Percepção de Cores , Análise Mutacional de DNA , Eletroculografia , Eletrorretinografia , Feminino , Genes Recessivos , Haplótipos , Humanos , Israel/epidemiologia , Masculino , Linhagem , Reação em Cadeia da Polimerase , Degeneração Retiniana/diagnóstico , Testes de Campo Visual , Iêmen/etnologia
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