RESUMO
Ten new and seventeen previously reported Enhanced S Cone Syndrome (ESCS) subjects were used to search for genetic heterogeneity. All subjects were diagnosed with ESCS on the basis of clinical, psychophysical and/or electroretinography testing using published criteria. Mutation analysis was performed on the NR2E3 nuclear receptor gene by single strand conformation analysis and direct sequencing, which revealed either homozygous (N=13) or compound heterozygous (N=11) mutations in 24 subjects (89%), heterozygous mutations in 2 subjects (7%) and no mutations in 1 subject (4%). Fifteen different mutations were identified, including six not previously reported. The subject (Patient A) with no detected NR2E3 mutation had features not usually associated with ESCS, in particular moderate rod photoreceptor function in peripheral retina and an abnormally thick retinal nerve fibre layer. Mutation analysis of the NRL, CRX, NR1D1 and THRB genes in this individual revealed a heterozygous one base-pair insertion in exon 2 of the NRL gene, which results in a predicted truncation of the NRL protein. Loss-of-function NRL alleles have not been described previously in humans, but since the same mutation was present in unaffected family members, it raises the possibility that the abnormal ESCS phenotype in Patient A may result from a digenic mechanism, with a heterozygous NRL mutation and a mutation in another unknown gene.
Assuntos
Anormalidades Múltiplas/genética , Proteínas de Ligação a DNA/genética , Oftalmopatias/genética , Proteínas do Olho/genética , Mutação/genética , Receptores Citoplasmáticos e Nucleares/genética , Fatores de Transcrição/genética , Anormalidades Múltiplas/fisiopatologia , Adolescente , Adulto , Alelos , Sequência de Aminoácidos , Sequência de Bases , Fatores de Transcrição de Zíper de Leucina Básica , Análise Mutacional de DNA , Eletrorretinografia , Éxons/genética , Oftalmopatias/fisiopatologia , Feminino , Heterogeneidade Genética , Testes Genéticos , Humanos , Masculino , Pessoa de Meia-Idade , Receptores Nucleares Órfãos , Fenótipo , Polimorfismo Conformacional de Fita Simples , SíndromeRESUMO
PURPOSE: To examine the effect of apolipoprotein E (APOE) alleles on age-related macular degeneration (AMD) risk and on age at diagnosis of AMD in a large patient cohort recruited from a single center. METHODS: The frequency of APOE alleles was analyzed in 632 unrelated AMD patients and 206 unrelated controls, all of whom were of white ancestry. The presence or absence of disease symptoms in all patients and controls was based on clinical examination and/or ophthalmic records. The association with APOE was explored in the context of AMD subtypes, family history status, possible interaction with smoking, and distribution of age at diagnosis of AMD. RESULTS: The frequency of the epsilon4 allele was significantly reduced in patients compared with controls (0.10 vs. 0.14, P < or = 0.02). Gender- and age-adjusted odds ratios indicated that epsilon4-carriers have significantly lower risk of developing AMD compared to epsilon3epsilon3 subjects (OR = 0.55, 95% CI: 0.37-0.82, P = 0.004). In the cohort, AMD patients with a positive family history exhibited a significant 3.5 years earlier age at diagnosis (P = 0.001); however, APOE alleles did not appear to modulate the age at diagnosis of AMD. CONCLUSIONS: The association between the APOE-epsilon4 allele and a reduced risk of AMD was established in a large cohort with sufficient statistical power. How distinct APOE alleles affect AMD susceptibility warrants further investigation.
Assuntos
Apolipoproteínas E/genética , Degeneração Macular/genética , Idoso , Alelos , Apolipoproteína E4 , Estudos de Coortes , DNA/análise , Feminino , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Fatores de RiscoRESUMO
Age-related macular degeneration (AMD) is a complex multifactorial disease that affects the central region of the retina. AMD is clinically heterogeneous, leading to geographic atrophy (GA) and/or choroidal neovascularization (CNV) at advanced stages. Considerable data exists in support of a genetic predisposition for AMD. Recent linkage studies have provided evidence in favor of several AMD susceptibility loci. We have performed a high-resolution (5-cM) genome scan of 412 affected relative pairs that were enriched for late-stage disease (GA and/or CNV). Nonparametric linkage analysis was performed using two different diagnostic criteria and also by dividing the affected individuals according to GA or CNV phenotype. Our results demonstrate evidence of linkage in regions that were suggested in at least one previous study at chromosomes 1q (236-240 cM in the Marshfield genetic map), 5p (40-50 cM), and 9q (111 cM). Multipoint analysis of affected relatives with CNV provided evidence of additional susceptibility loci on chromosomes 2p (10 cM) and 22q (25 cM). A recently identified Gln5345Arg change in HEMICENTIN-1 on chromosome 1q25 was not detected in 274 affected members in the restricted group with AMD, 346 additional patients with AMD, and 237 unaffected controls. Our results consolidate the chromosomal locations of several AMD susceptibility loci and, together with previous reports, should facilitate the search for disease-associated sequence variants.
