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1.
Hum Mutat ; 30(8): 1183-8, 2009 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-19431183

RESUMO

To assist in distinguishing disease-causing mutations from nonpathogenic polymorphisms, we developed an objective algorithm to calculate an "estimate of pathogenic probability" (EPP) based on the prevalence of a specific variation, its segregation within families, and its predicted effects on protein structure. Eleven missense variations in the RPE65 gene were evaluated in patients with Leber congenital amaurosis (LCA) using the EPP algorithm. The accuracy of the EPP algorithm was evaluated using a cell-culture assay of RPE65-isomerase activity The variations were engineered into plasmids containing a human RPE65 cDNA and the retinoid isomerase activity of each variant was determined in cultured cells. The EPP algorithm predicted eight substitution mutations to be disease-causing variants. The isomerase catalytic activities of these RPE65 variants were all less than 6% of wild-type. In contrast, the EPP algorithm predicted the other three substitutions to be non-disease-causing, with isomerase activities of 68%, 127%, and 110% of wild-type, respectively. We observed complete concordance between the predicted pathogenicities of missense variations in the RPE65 gene and retinoid isomerase activities measured in a functional assay. These results suggest that the EPP algorithm may be useful to evaluate the pathogenicity of missense variations in other disease genes where functional assays are not available.


Assuntos
Proteínas de Transporte/genética , Proteínas do Olho/genética , Mutação de Sentido Incorreto , Algoritmos , Sequência de Aminoácidos , Sequência de Bases , Biocatálise , Proteínas de Transporte/química , Proteínas de Transporte/fisiologia , Linhagem Celular , Primers do DNA , DNA Complementar , Proteínas do Olho/química , Proteínas do Olho/fisiologia , Feminino , Humanos , Masculino , Dados de Sequência Molecular , Mutagênese Sítio-Dirigida , Linhagem , Reação em Cadeia da Polimerase Via Transcriptase Reversa , cis-trans-Isomerases
2.
J Med Genet ; 46(5): 300-7, 2009 May.
Artigo em Inglês | MEDLINE | ID: mdl-19015224

RESUMO

BACKGROUND: Age related macular degeneration (AMD) is a leading cause of blindness. AMD is a complex disorder caused by genetic and environmental factors in which single nucleotide polymorphisms (SNPs) in the genes CFH and LOC387715/HTRA1/ARMS2 have prognostic importance for progression to advanced AMD (with visual loss). CFH may also have a pharmacogenetic role by affecting treatment response to widely used nutritional supplements. This paper examines other AMD susceptibility genes to determine if these genotypes influenced disease progression and treatment response. METHODS: Three cohorts, totalling 3137 individuals, were genotyped for SNPs in 13 genes previously published to be associated with advanced AMD (other than CFH and LOC387715/ARMS2/HTRA1). Those genes found associated were then evaluated for their involvement in disease progression. Interactions between the genes and with AREDS (Age-Related Eye Disease Study) nutritional supplements were investigated. RESULTS: Positive independent associations were noted in SNPs in the genes C2 (p = 0.0001, odds ratio (OR) 0.35, 95% confidence interval (CI) 0.2 to 0.6), CFB (p = 0.0001, OR 0.35, 95% CI 0.2 to 0.6), C3 (p = 0.0001, OR 3.91, 95% CI 1.94 to 7.88), APOE (epsilon4, p = 0.01, OR 0.50, 95% CI 0.29 to 0.86) and VEGFA (p = 0.01, OR 2.23, 95% CI 1.06 to 4.68). C2/CFB and C3 were independently related to progression from early/intermediate to advanced AMD with OR 0.32 (95% CI 0.14 to 0.73) and 3.32 (95% CI 1.46 to 7.59), respectively. Gene-gene and pharmacogenetic interactions were not observed. No preferential associations were observed with geographic atrophy or choroidal neovascularisation. CONCLUSION: This study provides insights into the genetic pathogenesis of AMD. Five genes have now been shown to be independently involved in progression from intermediate disease (before vision loss has occurred) to advanced disease in which blindness is frequent.


Assuntos
Complemento C2/genética , Complemento C3/genética , Fator H do Complemento/genética , Degeneração Macular/genética , Polimorfismo de Nucleotídeo Único , Idoso , Idoso de 80 Anos ou mais , Apolipoproteínas E/genética , Estudos de Coortes , Progressão da Doença , Feminino , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Humanos , Modelos Logísticos , Degeneração Macular/complicações , Degeneração Macular/patologia , Masculino , Pessoa de Meia-Idade , Razão de Chances , Fator A de Crescimento do Endotélio Vascular/genética , Baixa Visão/etiologia
4.
Br J Ophthalmol ; 89(9): 1115-9, 2005 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-16113362

RESUMO

BACKGROUND: The pattern dystrophies (PD) represent a clinically heterogeneous family of inherited macular diseases frequently caused by mutations in the peripherin/RDS gene. Most previous studies have detailed the clinical findings in single families, making it difficult to derive data from which progression and visual outcome can be generalised. METHODS: Families were ascertained and clinically evaluated including angiography and electrophysiology where appropriate. RESULTS: In each of the six families with autosomal dominant PD, a mutation in the peripherin/RDS gene was identified, including a novel Cys250Phe variant. These data suggest that the condition is characterised by the accumulation of yellow to grey subretinal flecks, followed by pigmentary change accompanied by patches of chorioretinal atrophy. Subsequently, 50% (16/32) of individuals with PD developed poor central vision because of chorioretinal geographic atrophy or subretinal neovascularisation. The risk of these complications appears to increase with age. CONCLUSION: PD should not necessarily be considered a benign condition. Instead, patients should be counselled that there is a significant chance of losing central vision in their later years. Some elderly patients with probands showing PD may be misdiagnosed with age related macular degeneration owing to the phenotypic similarities between these conditions in the advanced state.


Assuntos
Proteínas de Filamentos Intermediários/genética , Glicoproteínas de Membrana/genética , Proteínas do Tecido Nervoso/genética , Mutação Puntual , Degeneração Retiniana/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Corioide/patologia , Neovascularização de Coroide/patologia , Eletrorretinografia , Feminino , Humanos , Macula Lutea/patologia , Degeneração Macular/genética , Degeneração Macular/patologia , Masculino , Pessoa de Meia-Idade , Linhagem , Periferinas , Fenótipo , Retina/patologia , Degeneração Retiniana/patologia , Testes de Campo Visual
5.
Br J Ophthalmol ; 88(12): 1533-7, 2004 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-15548806

RESUMO

AIM: To describe the clinical characteristics and disease course of a large family with retinitis pigmentosa (RP) from an Arg135Leu change in rhodopsin. METHODS: 29 patients in this family were evaluated. Goldmann visual fields were performed on 14 affected individuals, Ganzfeld electroretinography (ERG) on eight individuals (11-56 years), and blood samples collected on 10 individuals (11-58 years). Patient visual field data were compared with previously reported patients with different rhodopsin mutations using linear regression. RESULTS: An Arg135Leu mutation was identified in rhodopsin. Distinct stages of clinical evolution were identified for this family ranging from normal, white dots, classic bone spicules and, finally, ending with extensive retinal pigment epithelium (RPE) atrophy. 9/16 patients over the age of 20 years also demonstrated marked macular atrophy. All patients who underwent full field ERG testing demonstrated non-recordable ERGs. The overall regression model comparing solid angles of visual fields from patients with rhodopsin mutations (Pro23His, Pro347Ala, Arg135Leu) shows significant effects for age (p = 0.0005), mutation (p = 0.0014), and interaction between age and mutation (p = 0.018) with an R(2) of 0.407. CONCLUSIONS: An Arg135Leu change in rhodopsin results in a severe form of RP that evolves through various fundus appearances that include white dots early in life and classic appearing RP later. This transmembrane change in rhodopsin proves to be more severe than in a family with an intradiscal change and a family with a cytoplasmic change.


Assuntos
Retinose Pigmentar/genética , Rodopsina/genética , Adolescente , Adulto , Arginina/genética , Criança , Eletrorretinografia/métodos , Saúde da Família , Feminino , Angiofluoresceinografia/métodos , Genótipo , Humanos , Leucina/genética , Masculino , Pessoa de Meia-Idade , Mutação/genética , Linhagem , Fenótipo , Retinose Pigmentar/patologia , Retinose Pigmentar/fisiopatologia , Acuidade Visual/fisiologia , Testes de Campo Visual/métodos , Campos Visuais/fisiologia
6.
Br J Ophthalmol ; 86(6): 658-62, 2002 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-12034689

RESUMO

BACKGROUND/AIMS: Few studies have reported on the change in visual acuity (VA) in patients with choroideraemia. In order to determine the degree and rate of VA impairment associated with this disease, the central VA was analysed in a large group of patients with choroideraemia. METHODS: The authors completed a retrospective, cross sectional review of 115 patients with choroideraemia from three tertiary care centres. A longitudinal analysis was performed on 45 of these patients who met the inclusion criteria of at least three visits over a minimum period of 4.5 years. Multiple linear regression analysis was used to explore the 5 year rate of VA change while controlling for initial VA and initial age. Multiple logistic regression was also used to investigate VA impairment. RESULTS: In the cross sectional group (n = 115), 84% (87/103) of patients under the age of 60 had a VA of 20/40 or better while 33% (4/12) of patients 60 years of age or older had a VA of 20/200 or worse at their most recent visit. The majority of the patients (93%) in the longitudinal subgroup of 45 patients had a VA of 20/30 or better at their initial visit. The mean 5 year rate of VA change was 0.09 logMAR equivalent (approximately one line on the Lighthouse chart). CONCLUSION: In this cohort of patients with choroideraemia, there was typically a slow rate of VA loss and the prognosis for central VA retention was, as a group, favourable until the seventh decade.


Assuntos
Coroideremia/fisiopatologia , Transtornos da Visão/etiologia , Acuidade Visual , Adolescente , Adulto , Idoso , Criança , Coroideremia/complicações , Estudos Transversais , Progressão da Doença , Humanos , Modelos Lineares , Estudos Longitudinais , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Transtornos da Visão/fisiopatologia
7.
J Med Genet ; 38(6): 381-4, 2001 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-11389162

RESUMO

OBJECTIVE: Autosomal dominant drusen is of particular interest because of its phenotypic similarity to age related macular degeneration. Currently, mutation R345W of EFEMP1 and, in a single pedigree, linkage to chromosome 6q14 have been causally related to the disease. We proposed to investigate and quantify the roles of EFEMP1 and the 6q14 locus in dominant drusen patients from the UK and USA. DESIGN: Molecular genetic analysis. PARTICIPANTS: Ten unrelated families and 17 young drusen patients. MAIN OUTCOME MEASURES: Exons 1 and 2 of EFEMP1 were characterised by 5' rapid amplification of cDNA ends and direct sequencing. Exons 1-12 of EFEMP1 were then investigated for mutation by direct sequencing. A HpaII restriction digest test was constructed to detect the EFEMP1 R345W mutation. Marker loci spanning the two dominant drusen linked loci were used to generate haplotype data. RESULTS: Only seven of the 10 families (70%) and one of the 17 sporadic patients (6%) had the R345W mutation. The HpaII restriction digest test was found to be a reliable and quick method for detecting this. No other exonic or splice site mutation was identified. Of the three families without EFEMP1 mutation, two were linked to the 2p16 region. CONCLUSIONS: EFEMP1 R345W accounts for only a proportion of the dominant drusen phenotype. Importantly, other families linked to chromosome 2p16 raise the possibility of EFEMP1 promoter sequence mutation or a second dominant drusen gene at this locus. Preliminary haplotype data suggest that the disease gene at the 6q14 locus is responsible for only a minority of dominant drusen cases.


Assuntos
Proteínas da Matriz Extracelular/genética , Genes Dominantes , Polimorfismo de Nucleotídeo Único , Drusas Retinianas/genética , Adulto , Cromossomos Humanos Par 2 , Cromossomos Humanos Par 6 , Estudos de Coortes , Feminino , Ligação Genética , Variação Genética , Haplótipos , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Radiografia , Drusas Retinianas/diagnóstico por imagem
8.
Invest Ophthalmol Vis Sci ; 42(6): 1179-89, 2001 May.
Artigo em Inglês | MEDLINE | ID: mdl-11328725

RESUMO

PURPOSE: To assess the allelic variation of the ATP-binding transporter protein (ABCA4). METHODS: A combination of single-strand conformation polymorphism (SSCP) and automated DNA sequencing was used to systematically screen this gene for sequence variations in 374 unrelated probands with a clinical diagnosis of Stargardt disease, 182 patients with age-related macular degeneration (AMD), and 96 normal subjects. RESULTS: There was no significant difference in the proportion of any single variant or class of variant between the control and AMD groups. In contrast, truncating variants, amino acid substitutions, synonymous codon changes, and intronic variants were significantly enriched in patients with Stargardt disease when compared with their presence in subjects without Stargardt disease (Kruskal-Wallis P < 0.0001 for each variant group). Overall, there were 2480 instances of 213 different variants in the ABCA4 gene, including 589 instances of 97 amino acid substitutions, and 45 instances of 33 truncating variants. CONCLUSIONS: Of the 97 amino acid substitutions, 11 occurred at a frequency that made them unlikely to be high-penetrance recessive disease-causing variants (HPRDCV). After accounting for variants in cis, one or more changes that were compatible with HPRDCV were found on 35% of all Stargardt-associated alleles overall. The nucleotide diversity of the ABCA4 coding region, a collective measure of the number and prevalence of polymorphic sites in a region of DNA, was found to be 1.28, a value that is 9 to 400 times greater than that of two other macular disease genes that were examined in a similar fashion (VMD2 and EFEMP1).


Assuntos
Transportadores de Cassetes de Ligação de ATP/genética , Alelos , Variação Genética , Degeneração Macular/genética , Adulto , Humanos , Desequilíbrio de Ligação , Polimorfismo Genético , Polimorfismo Conformacional de Fita Simples , Análise de Sequência de DNA
9.
Hum Genet ; 108(2): 91-7, 2001 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-11281458

RESUMO

Incomplete X-linked congenital stationary night blindness (CSNB) is a recessive, non-progressive eye disorder characterized by abnormal electroretinogram and psychophysical testing and can include impaired night vision, decreased visual acuity, myopia, nystagmus, and strabismus. Including the 20 families previously reported (Bech-Hansen et al. 1998b), we have now analyzed patients from a total of 36 families with incomplete CSNB and identified 20 different mutations in the calcium channel gene CACNA1F. Three of the mutations account for incomplete CSNB in two or more families, and a founder effect is clearly demonstrable for one of these mutations. Of the 20 mutations identified, 14 (70%) are predicted to cause premature protein truncation and six (30%) to cause amino acid substitutions or deletions at conserved positions in the alpha1F protein. In characterizing transcripts of CACNA1F we have identified several splice variants and defined a prototypical sequence based on the location of mutations in splice variants and comparison with the mouse orthologue, Cacnalf.


Assuntos
Canais de Cálcio Tipo L , Canais de Cálcio/genética , Ligação Genética , Mutação de Sentido Incorreto , Cegueira Noturna/genética , Splicing de RNA , Cromossomo X , Sequência de Aminoácidos , Animais , Sequência de Bases , DNA Complementar , Humanos , Camundongos , Dados de Sequência Molecular , Cegueira Noturna/congênito , Homologia de Sequência de Aminoácidos
10.
Arch Ophthalmol ; 119(4): 564-70, 2001 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-11296022

RESUMO

OBJECTIVES: To characterize a disease-associated haplotype in 7 families with autosomal dominant Stargardt-like macular dystrophy and to determine whether these families share a common ancestor. METHODS: Twenty-five polymorphic DNA markers spanning known dominant Stargardt-like gene loci were used to determine the haplotype associated with disease. In addition, an extensive genealogical investigation searching for a common ancestor shared by all of the 7 families was performed. RESULTS: We clinically evaluated 171 patients and genotyped 145 samples. The same DNA haplotype on chromosome 6q16 was shared by all evaluated affected members within the 7 families. In addition, we were able to genealogically join all of the families into one larger family consisting of 31 branches and 2314 individuals. Twenty-seven branches have known living descendants, with 7 branches having affected family members. In addition, we refined the critical region for the gene to approximately 1000 kilobases (kb) and eliminated part or all of 9 candidate disease-causing genes. CONCLUSIONS: Our study indicates that most reported cases of autosomal dominant Stargardt-like macular dystrophy in North America are part of a single larger family associated with a gene locus on chromosome 6q16. Furthermore, the DNA haplotype associated with disease is useful in excluding individuals with phenotypically similar retinal conditions. CLINICAL RELEVANCE: The disease-associated haplotype allows for more accurate genetic counseling to be given to individuals with a Stargardt-like phenotype inherited in an autosomal dominant pattern.


Assuntos
Efeito Fundador , Genes Dominantes , Heterogeneidade Genética , Degeneração Macular/genética , Mapeamento Cromossômico , Cromossomos Humanos Par 6/genética , DNA/análise , Feminino , Genealogia e Heráldica , Ligação Genética/genética , Marcadores Genéticos , Haplótipos , Humanos , Masculino , Linhagem
11.
Arch Ophthalmol ; 119(3): 415-20, 2001 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-11231775

RESUMO

OBJECTIVES: To test the hypothesis that mutations in the CRB1 gene cause Leber congenital amaurosis (LCA) and, if so, to describe the ocular phenotype of patients with LCA who harbor CRB1 sequence variations. PATIENTS: One hundred ninety probands with a clinical diagnosis of LCA were selected from a cohort of 233 probands ascertained in 5 different countries. The remaining 43 probands (18%) were excluded because they harbored sequence variations in previously identified LCA genes. METHODS: One hundred ninety unrelated individuals with LCA were screened for coding sequence mutations in the CRB1 gene with single-strand conformation polymorphism analysis followed by automated DNA sequencing. RESULTS: Twenty-one of the 190 probands (9% of the total cohort of 233) and 2 (1.4%) of 140 controls harbored amino acid-altering sequence variations in the CRB1 gene (P =.003). CONCLUSIONS: In our cohort of patients with LCA, coding sequence variations were observed in the CRB1 gene more frequently than in any of the other 5 known LCA-associated genes. Likely disease-causing sequence variations have now been identified in 64 (28%) of 233 subjects in this cohort. CLINICAL RELEVANCE: Molecular diagnosis can confirm and clarify the diagnosis in an increasing fraction of patients with LCA. As genotype data accumulate, clinical phenotypes associated with specific mutations may be established. This will facilitate the counseling of patients regarding their visual prognosis and the likelihood of associated systemic anomalies.


Assuntos
Cegueira/genética , Proteínas de Drosophila , Proteínas de Membrana/genética , Mutação , Atrofias Ópticas Hereditárias/genética , Adolescente , Adulto , Cegueira/congênito , Criança , Pré-Escolar , Estudos de Coortes , DNA/análise , Primers do DNA/química , Humanos , Lactente , Pessoa de Meia-Idade , Atrofias Ópticas Hereditárias/patologia , Reação em Cadeia da Polimerase , Polimorfismo Conformacional de Fita Simples , Acuidade Visual
12.
Artigo em Inglês | MEDLINE | ID: mdl-11201911

RESUMO

PURPOSE: To determine the frequency of Usher's syndrome and other ocular disease in students receiving special education services for the deaf in Oregon and to assess the amount of existing ophthalmologic surveillance of this population. A special emphasis was placed on screening for Usher's syndrome. METHODS: From 1980-1990, a prospective two-center visual screening program of 231 deaf students in schools throughout Oregon was conducted using an ophthalmic questionnaire, complete eye examinations, and electroretinography. Students were between the ages of 10 and 21 years and participated on a volunteer basis. Findings for etiology and severity of visual loss and the scope of ophthalmologic surveillance within this population were analyzed. RESULTS: Two hundred seventeen of the 231 students examined received electroretinograms. Significant ocular pathology was found in 111 (48%) of the students. The most common diagnoses were congenital rubella (21%), significant uncorrected ametropia (16%), and ocular hypertension (9%). Five students were diagnosed with Usher's syndrome. Of the students with significant ocular pathology, only 37% were actively followed by an ophthalmologist. CONCLUSION: Deaf students in Oregon's schools had a high frequency of eye disease. Early diagnosis and treatment of eye disease in this population could benefit the quality of life of these students. This study alerted the providers of special education services for the deaf and the ophthalmologic community in Oregon of the need for better eye care for these students.


Assuntos
Oftalmopatias/epidemiologia , Pessoas com Deficiência Auditiva/estatística & dados numéricos , Seleção Visual , Adolescente , Adulto , Criança , Eletrorretinografia , Oftalmopatias/diagnóstico , Humanos , Oregon/epidemiologia , Estudos Prospectivos , Qualidade de Vida , Instituições Acadêmicas , Estudantes , Inquéritos e Questionários
13.
Ophthalmology ; 107(12): 2256-66, 2000 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-11097607

RESUMO

PURPOSE: To clarify the pathogenesis of late-onset retinal degeneration (L-ORD), an autosomal dominant disorder characterized by thick deposits of lipid-rich material between the retinal pigment epithelium (RPE) and Bruch's membrane. STUDY DESIGN: Comparative clinicopathologic case report and case series. TISSUES: Eyes of an 82-year-old L-ORD eye donor and an age-matched control. SUBJECTS: Five descendants of the eye donor and his affected sister. METHODS: The eyes were processed for histopathologic examination, including electron microscopy and immunohistochemistry. Family members were examined clinically and with retinal function tests. RESULTS: The L-ORD eye had sub-RPE deposits that were positive for lipid, including esterified and unesterified cholesterol. The deposits were thinnest in the macula, which retained the highest percentage of photoreceptors. In the periphery, RPE thinning and photoreceptor loss correlated with thickness of the sub-RPE deposits. The eye donor was asymptomatic until his late 50s, when he developed problems with adapting to darkness. At age 68, the eye donor had normal acuity but a midperipheral scotoma and subnormal electroretinograms (ERGs); visual loss was progressive. The five descendants (at the time of examination ages 44-58) of the eye donor and his affected sister, who were at 50/50 risk of inheriting L-ORD, had normal ERGs, but four showed defects in dark adaptation. The dark adaptation abnormalities had a distribution similar to the thickness of the sub-RPE deposits in the eye donor, with slow kinetics in the midperiphery and normal kinetics centrally. CONCLUSIONS: The L-ORD donor eye differed from a previous case in the regional distribution of sub-RPE deposits and photoreceptors. In the next generation of this L-ORD family, the first expression of disease, abnormal dark adaptation, mirrored the regional distribution of the deposits in the donor eye. The fine structure and staining characteristics of the sub-RPE deposits in L-ORD resemble those in age-related macular degeneration and Sorsby fundus dystrophy.


Assuntos
Oftalmopatias Hereditárias/patologia , Células Fotorreceptoras de Vertebrados/patologia , Epitélio Pigmentado Ocular/patologia , Retina/fisiologia , Degeneração Retiniana/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Apolipoproteínas/metabolismo , Lâmina Basilar da Corioide/patologia , Adaptação à Escuridão , Eletrorretinografia , Oftalmopatias Hereditárias/genética , Oftalmopatias Hereditárias/metabolismo , Oftalmopatias Hereditárias/fisiopatologia , Feminino , Filipina/metabolismo , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Linhagem , Células Fotorreceptoras de Vertebrados/metabolismo , Células Fotorreceptoras de Vertebrados/ultraestrutura , Epitélio Pigmentado Ocular/metabolismo , Epitélio Pigmentado Ocular/ultraestrutura , Degeneração Retiniana/genética , Degeneração Retiniana/metabolismo , Degeneração Retiniana/fisiopatologia , Doadores de Tecidos , Acuidade Visual , Campos Visuais
14.
Nat Genet ; 26(3): 319-23, 2000 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-11062471

RESUMO

During development, visual photoreceptors, bipolar cells and other neurons establish connections within the retina enabling the eye to process visual images over approximately 7 log units of illumination. Within the retina, cells that respond to light increment and light decrement are separated into ON- and OFF-pathways. Hereditary diseases are known to disturb these retinal pathways, causing either progressive degeneration or stationary deficits. Congenital stationary night blindness (CSNB) is a group of stable retinal disorders that are characterized by abnormal night vision. Genetic subtypes of CSNB have been defined and different disease actions have been postulated. The molecular bases have been elucidated in several subtypes, providing a better understanding of the disease mechanisms and developmental retinal neurobiology. Here we have studied 22 families with 'complete' X-linked CSNB (CSNB1; MIM 310500; ref. 4) in which affected males have night blindness, some photopic vision loss and a defect of the ON-pathway. We have found 14 different mutations, including 1 founder mutation in 7 families from the United States, in a novel candidate gene, NYX. NYX, which encodes a glycosylphosphatidyl (GPI)-anchored protein called nyctalopin, is a new and unique member of the small leucine-rich proteoglycan (SLRP) family. The role of other SLRP proteins suggests that mutant nyctalopin disrupts developing retinal interconnections involving the ON-bipolar cells, leading to the visual losses seen in patients with complete CSNB.


Assuntos
Proteínas do Olho/genética , Genes , Interneurônios/patologia , Cegueira Noturna/genética , Proteoglicanas/genética , Cromossomo X/genética , Adulto , Motivos de Aminoácidos , Sequência de Aminoácidos , Análise Mutacional de DNA , DNA Complementar/genética , Etiquetas de Sequências Expressas , Proteínas do Olho/química , Proteínas do Olho/fisiologia , Perfilação da Expressão Gênica , Glicosilfosfatidilinositóis/metabolismo , Humanos , Interneurônios/metabolismo , Rim/metabolismo , Leucina/análise , Masculino , Dados de Sequência Molecular , Cegueira Noturna/classificação , Especificidade de Órgãos , Linhagem , Proteoglicanas/química , Proteoglicanas/deficiência , Proteoglicanas/fisiologia , Sequências Repetitivas de Aminoácidos , Retina/patologia , Células Ganglionares da Retina/metabolismo , Alinhamento de Sequência , Homologia de Sequência de Aminoácidos , Transmissão Sináptica/fisiologia , Visão Ocular/fisiologia
15.
Invest Ophthalmol Vis Sci ; 41(11): 3268-77, 2000 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-11006213

RESUMO

PURPOSE: To investigate the function and pathogenicity of HRG4, a photoreceptor synaptic protein homologous to the Caenorhabditis elegans neuroprotein UNC119. METHODS: HRG4 was screened for mutations in patients with various retinopathies, and a transgenic mouse model was constructed and analyzed based on a mutation found. RESULTS: A heterozygous premature termination codon mutation was found in a 57-year-old woman with late-onset cone-rod dystrophy. In some transgenic mice carrying the identical mutation, age-dependent fundus lesions developed accompanied by electroretinographic changes consistent with defects in photoreceptor synaptic transmission (depressed b-wave, normal c-wave), and retinal degeneration occurred with marked synaptic and possible transsynaptic degeneration. CONCLUSIONS: HRG4, the only synaptic protein known to be highly enriched in photoreceptor ribbon synapses, is now shown to be pathogenic when mutated.


Assuntos
Proteínas do Olho/genética , Mutação , Células Fotorreceptoras de Vertebrados/patologia , Retinose Pigmentar/genética , Proteínas Adaptadoras de Transdução de Sinal , Adulto , Animais , Northern Blotting , Western Blotting , Modelos Animais de Doenças , Eletrorretinografia , Feminino , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Pessoa de Meia-Idade , Células Fotorreceptoras de Vertebrados/fisiologia , Retinose Pigmentar/patologia , Retinose Pigmentar/fisiopatologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Campos Visuais
16.
Arch Ophthalmol ; 118(9): 1269-76, 2000 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-10980774

RESUMO

OBJECTIVES: To report the clinical characteristics of a family with autosomal dominant retinitis pigmentosa caused by a proline-to-alanine mutation at codon 23 (Pro23Ala) of the rhodopsin gene and to compare this phenotype with that associated with the more common proline-to-histidine mutation at codon 23 (Pro23His). METHODS: We examined 6 patients within a single pedigree. The electroretinograms (ERGs) of 35 patients with known Pro23His mutations and of 22 healthy individuals were reviewed. Scotopic dim flash-response amplitudes, maximum combined-response amplitudes, and photopic-response amplitudes from the ERGs of these patients were plotted against age. The ERG indices of 5 individuals in the Pro23Ala family were compared with those of the patients with Pro23His mutations and of healthy individuals. Multiple linear regression was performed to evaluate the effect of age and mutation type on amplitudes. Mutation detection was performed using single-strand conformation polymorphism analysis, followed by automated DNA sequencing. RESULTS: Patients with the Pro23Ala mutation have a clinical phenotype characterized by onset of symptoms in the second to fourth decades of life, loss of superior visual field with relatively well-preserved inferior fields, and mild nyctalopia. Comparison with patients with the Pro23His mutation demonstrates statistically significant differences (P<.001) in responses to dim flash, maximum combined, and photopic responses between patients with these mutations after controlling for the effects of age. Patients with Pro23Ala mutations were less affected by ERG criteria than patients with Pro23His mutations. Patients with Pro23Ala mutations also differed significantly from healthy patients in all ERG indices examined (P<.001), after controlling for age. CONCLUSION: We describe a rare mutation in codon 23 of rhodopsin causing autosomal dominant retinitis pigmentosa. The retinal dystrophy associated with the Pro23Ala mutation is characteristically mild in presentation and course, with greater preservation of ERG amplitudes than the more prevalent Pro23His mutation. Arch Ophthalmol. 2000;118:1269-1276


Assuntos
Eletrorretinografia , Mutação Puntual , Retina/fisiopatologia , Retinose Pigmentar/genética , Rodopsina/genética , Adolescente , Adulto , Idoso , Criança , Códon , Análise Mutacional de DNA , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Fenótipo , Estimulação Luminosa , Polimorfismo Conformacional de Fita Simples , Retina/patologia , Retinose Pigmentar/patologia , Retinose Pigmentar/fisiopatologia , Acuidade Visual , Testes de Campo Visual , Campos Visuais
17.
Invest Ophthalmol Vis Sci ; 41(7): 1898-908, 2000 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-10845615

RESUMO

PURPOSE: To determine the disease expression in heterozygotes for mutations in the RP1 gene, a newly identified cause of autosomal dominant retinitis pigmentosa (adRP). METHODS: Screening strategies were used to detect disease-causing mutations in the RP1 gene, and detailed studies of phenotype were performed in a subset of the detected RP1 heterozygotes using electroretinography (ERG), psychophysics, and optical coherence tomography (OCT). RESULTS: Seventeen adRP families had heterozygous RP1 changes. Thirteen families had the Arg677ter mutation, whereas four others had one of the following: Pro658 (1-bp del), Ser747 (1-bp del), Leu762-763 (5-bp del), and Tyr1053 (1-bp del). In Arg677ter RP1 heterozygotes, there was regional retinal variation in disease, with the far peripheral inferonasal retina being most vulnerable; central and superior temporal retinal regions were better preserved. The earliest manifestation of disease was rod dysfunction, detectable as reduced rod ERG photoresponse maximum amplitude, even in heterozygotes with otherwise normal clinical, functional, and OCT cross-sectional retinal imaging results. At disease stages when cone abnormalities were present, there was greater rod than cone dysfunction. Patients with the RP1 frameshift mutations showed similarities in phenotype to those with the Arg677ter mutation. CONCLUSIONS: Earliest disease expression of RP1 gene mutations causing adRP involves primarily rod photoreceptors, and there is a gradient of vulnerability of retinopathy with more pronounced effects in the inferonasal peripheral retina. At other disease stages, cone function is also affected, and severe retina-wide degeneration can occur. The nonpenetrance or minimal disease expression in some Arg677ter mutation-positive heterozygotes suggests important roles for modifier genes or environmental factors in RP1-related disease.


Assuntos
Proteínas do Olho/genética , Mutação , Retinose Pigmentar/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Adaptação à Escuridão/fisiologia , Eletrorretinografia , Feminino , Humanos , Masculino , Proteínas Associadas aos Microtúbulos , Pessoa de Meia-Idade , Fenótipo , Células Fotorreceptoras de Vertebrados/fisiologia , Retinose Pigmentar/fisiopatologia , Tomografia/métodos , Campos Visuais/fisiologia
18.
Invest Ophthalmol Vis Sci ; 41(6): 1291-6, 2000 May.
Artigo em Inglês | MEDLINE | ID: mdl-10798642

RESUMO

PURPOSE: To assess the allelic variation of the VMD2 gene in patients with Best disease and age-related macular degeneration (AMD). METHODS: Three hundred twenty-one AMD patients, 192 ethnically similar control subjects, 39 unrelated probands with familial Best disease, and 57 unrelated probands with the ophthalmoscopic findings of Best disease but no family history were screened for sequence variations in the VMD2 gene by single-strand conformation polymorphism (SSCP) analysis. Amplimers showing a bandshift were reamplified and sequenced bidirectionally. In addition, the coding regions of the VMD2 gene were completely sequenced in six probands with familial Best disease who showed no SSCP shift. RESULTS: Forty different probable or possible disease-causing mutations were found in one or more Best disease or AMD patients. Twenty-nine of these variations are novel. Of the 39 probands with familial Best disease, mutations were detected in all 39 (33 by SSCP and 6 by DNA sequencing). SSCP screening of the 57 probands with a clinical diagnosis of Best disease but no family history revealed 16 with mutations. Mutations were found in 5 of 321 AMD patients (1.5%), a fraction that was not significantly greater than in control individuals (0/192, 0%). CONCLUSIONS: Patients with the clinical diagnosis of Best disease are significantly more likely to have a mutation in the VMD2 gene if they also have a positive family history. These findings suggest that a small fraction of patients with the clinical diagnosis of AMD may actually have a late-onset variant of Best disease, whereas at the same time, a considerable fraction of isolated patients with the ophthalmoscopic features of Best disease are probably affected with some other macular disease.


Assuntos
Alelos , Proteínas do Olho/genética , Variação Genética/genética , Degeneração Macular/genética , Mutação Puntual , Adulto , Idoso , Bestrofinas , Criança , Canais de Cloreto , Análise Mutacional de DNA , Primers do DNA/química , Feminino , Humanos , Degeneração Macular/diagnóstico , Masculino , Linhagem , Polimorfismo Conformacional de Fita Simples , Degeneração Retiniana/diagnóstico , Degeneração Retiniana/genética , Análise de Sequência de DNA
19.
Arch Ophthalmol ; 118(4): 538-43, 2000 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-10766140

RESUMO

OBJECTIVE: To assess the frequency of mutations in the CRX, GUCY2D, and RPE65 genes in patients with Leber congenital amaurosis (LCA). PATIENTS: One hundred seventy-six probands with a clinical diagnosis of LCA were from 9 countries, with the largest subgroup being 39 probands from India. METHODS: Samples were screened with single-strand conformation polymorphism analysis followed by DNA sequencing of 3 genes (CRX, GUCY2D, and RPE65) known to be associated with LCA. RESULTS: Of the 176 probands, 28 (15.9%) harbored possible disease-causing mutations. The relative contribution of each gene to the total number of mutations was as follows: CRX, 2.8%; GUCY2D, 6.3%; and RPE65, 6.8%. No patients who harbored mutations in these genes had associated systemic abnormalities. Molecular diagnosis allowed definitive genetic counseling in a family affected with Best disease and LCA. CONCLUSIONS: Molecular diagnosis may be of benefit to patients affected with LCA. The relative paucity of mutations found in this study suggests that more LCA-associated genes remain to be discovered. CLINICAL RELEVANCE: Molecular diagnosis can confirm and clarify the diagnosis of LCA. As genotype data accumulate, clinical phenotypes associated with specific mutations will be established. This will facilitate the counseling of patients on their visual prognosis and the likelihood of associated systemic anomalies.


Assuntos
Cegueira/genética , DNA/análise , Proteínas do Olho/genética , Guanilato Ciclase/genética , Proteínas de Homeodomínio/genética , Atrofias Ópticas Hereditárias/genética , Proteínas/genética , Transativadores/genética , Adolescente , Adulto , Cegueira/congênito , Cegueira/diagnóstico , Proteínas de Transporte , Criança , Pré-Escolar , Análise Mutacional de DNA , Feminino , Frequência do Gene , Aconselhamento Genético , Humanos , Lactente , Masculino , Atrofias Ópticas Hereditárias/diagnóstico , Linhagem , Polimorfismo Conformacional de Fita Simples , cis-trans-Isomerases
20.
Am J Hum Genet ; 66(4): 1432-6, 2000 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-10739768

RESUMO

Congenital cataracts are a common major abnormality of the eye that frequently cause blindness in infants. At least one-third of all cases are familial; autosomal-dominant congenital cataract appears to be the most-common familial form in the Western world. Elsewhere, in family ADCC-3, we mapped an autosomal-dominant cataract gene to chromosome 3q21-q22, near the gene that encodes a lens-specific beaded filament protein gene, BFSP2. By sequencing the coding regions of BFSP2, we found that a deletion mutation, DeltaE233, is associated with cataracts in this family. This is the first report of an inherited cataract that is caused by a mutation in a cytoskeletal protein.


Assuntos
Catarata/congênito , Catarata/genética , Proteínas do Olho/genética , Genes Dominantes/genética , Proteínas de Filamentos Intermediários/genética , Deleção de Sequência/genética , Sequência de Aminoácidos , Catarata/fisiopatologia , Pré-Escolar , Mapeamento Cromossômico , Cromossomos Humanos Par 3/genética , Análise Mutacional de DNA , Éxons/genética , Proteínas do Olho/química , Saúde da Família , Feminino , Humanos , Proteínas de Filamentos Intermediários/química , Íntrons/genética , Masculino , Dados de Sequência Molecular , Estrutura Secundária de Proteína
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