RESUMEN
PURPOSE: Esotropia is a feature of albinism. Amongst esotropic patients there may be mild unrecognised albinos. Oculocutaneous albinism shares several clinical features with congenital esotropia. It is well known that mammals with oculocutaneous albinism have misrouted retinal ganglion cell axons, most likely caused by the absence of melanin or DOPA during development. We investigated the hypothesis that mutations in the albinism genes Tyrosinase, the P Gene, and TYRP1 may also be responsible for congenital esotropia via a similar mechanism. METHODS: We screened these three genes in 21 families with congenital esotropia using single stranded conformational polymorphism analysis. RESULTS: No rare sequence variants segregating with esoptopia were detected. A novel silent mutation of the TYRP1 gene was identified in one pedigree but is not likely to be causative. Several previously reported common polymorphisms were detected but do not segregate with disease in this population. CONCLUSIONS: Rare mutations of these genes do not appear to be responsible for congenital esotropia. Although we found no evidence for segregation of common variants with disease, these require further investigation for a possible contribution to a complex threshold model. Several lines of evidence indicate a genetic componenet of congenital esotropia, however, this is the first investigation of candidate genes for this disorder.
Asunto(s)
Albinismo Oculocutáneo/genética , Proteínas Portadoras/genética , Esotropía/congénito , Glicoproteínas de Membrana , Proteínas de la Membrana/genética , Proteínas de Transporte de Membrana , Monofenol Monooxigenasa/genética , Mutación , Oxidorreductasas , Proteínas/genética , Cartilla de ADN/química , Humanos , Polimorfismo de Longitud del Fragmento de Restricción , Polimorfismo Conformacional Retorcido-Simple , Análisis de Secuencia de ADNRESUMEN
Primary open-angle glaucoma (POAG) is genetically heterogeneous, with 6 named POAG loci GLC1A-F mapped and genes myocilin (MYOC) and optineurin (OPTN) identified at 2 of the loci. Using penetrance-model-free methods, we screened the POAG loci GLC1A-F in an extended Australian pedigree, using 3-5 markers within each locus. p values of less than 0.05 were obtained empirically using SimWalk2 and exactly using Genehunter for 2 markers within the GLC1B region on chromosome 2. Fine mapping of this region produced p values of 0.01 or less at 5 markers flanked by D2S1897 and D2S2269. The 9 cM haplotype of interest overlaps the original GLC1B region. These results provide supportive evidence for the GLC1B locus on chromosome 2cen-q13 and verify the existence of POAG susceptibility gene in this region, increasing the likelihood of gene identification.
Asunto(s)
Proteínas del Citoesqueleto/genética , ADN/genética , Proteínas del Ojo/genética , Ligamiento Genético , Glaucoma de Ángulo Abierto/genética , Glicoproteínas/genética , Adulto , Edad de Inicio , Anciano , Proteínas de Ciclo Celular , Cromosomas Humanos Par 2/genética , Femenino , Predisposición Genética a la Enfermedad , Glaucoma de Ángulo Abierto/epidemiología , Haplotipos , Humanos , Masculino , Proteínas de Transporte de Membrana , Persona de Mediana Edad , Linaje , Reacción en Cadena de la Polimerasa , Tasmania/epidemiología , Factor de Transcripción TFIIIA/genéticaRESUMEN
OBJECTIVE: To describe the association between sex, smoking, physical activity, occupation, and previous digit fracture and hand osteoarthritis (OA). METHODS: Cross sectional study of 522 subjects from 101 Tasmanian families (348 women, 174 men). Hand OA was assessed by 2 observers using the OARSI atlas for joint space narrowing and osteophytes at distal interphalangeal (DIP) and carpometacarpal joints as well as a score for Heberden's nodes based on hand photography. A structured questionnaire collected information regarding physical activity, sport participation, occupation, and smoking history. RESULTS: Women had a higher prevalence of hand OA and the increase with age was significantly higher for women at all sites (all p < 0.05). Ever smoking was associated with less frequent (OR 0.59, 95% CI 0.38, 0.92) and less severe Heberden's nodes (beta -0.60, 95% CI -1.03, -0.17), but not radiological disease. Recall of occupation, physical activity, and sport participation between the ages of 20 and 40 years had no association with the prevalence or severity of hand OA, while self-reported digital fracture was significantly associated with more common (OR 2.42, 95% CI 1.22, 4.83) and severe DIP joint disease (beta +3.92, 95% CI +1.50, +6.36). No factors were associated with carpometacarpal disease. CONCLUSION: In this sample, women had a higher prevalence of hand OA at all sites as well as greater severity and a steeper age gradient (implying higher incidence rates). Smoking may decrease the risk of Heberden's nodes while having no effect on radiological hand OA, suggesting a differential effect possibly at the time of disease onset. With the exception of digital fracture, these data do not support a causal role for occupation or activity in earlier life with regard to hand OA.
Asunto(s)
Mano , Estilo de Vida , Osteoartritis/epidemiología , Factores Sexuales , Fumar , Adulto , Anciano , Anciano de 80 o más Años , Estudios Transversales , Femenino , Traumatismos de los Dedos/complicaciones , Traumatismos de los Dedos/epidemiología , Articulaciones de los Dedos/diagnóstico por imagen , Articulaciones de los Dedos/patología , Fracturas Óseas/complicaciones , Mano/diagnóstico por imagen , Mano/patología , Humanos , Masculino , Persona de Mediana Edad , Osteoartritis/diagnóstico por imagen , Osteoartritis/etiología , Prevalencia , Radiografía , Nódulo Reumatoide/diagnóstico por imagen , Nódulo Reumatoide/epidemiología , Nódulo Reumatoide/patología , Factores de Riesgo , Encuestas y Cuestionarios , Tasmania/epidemiologíaRESUMEN
Recent advances have enabled quite accurate estimation by spectrophotometry of the density of cutaneous melanin. The relation between skin cancers and this objective measure of skin phenotype is examined here. For this purpose, a population-based case-control study of subjects aged 20-59 years of northern European ancestry was conducted in Tasmania, Australia. Cases (n = 244) of cutaneous malignant melanoma during 1998-1999, and a sample of cases of basal cell carcinoma (n = 220) and squamous cell carcinoma (n = 195) of the skin were identified from cancer registrations. Controls (n = 483) were selected from a comprehensive population listing. Melanin at the upper inner arm was estimated from skin reflectance of light of 400 and 420 nm wavelengths. For melanoma, basal cell carcinoma, and squamous cell carcinoma, respectively, the odds ratios comparing the least with the highest of four melanin categories were 6.2 (95% confidence interval (CI): 2.3, 16.6), 6.3 (95% CI: 2.6, 15.1), and 4.2 (95% CI: 1.7, 10.8) for men and 1.9 (95% CI: 1.0, 3.7), 1.4 (95% CI: 0.7, 3.0), and 0.7 (95% CI: 0.3, 1.7) for women. The gender differences were not due to disparities in site of occurrence or (for melanoma) in thickness of the lesion. The authors conclude that, particularly for men, cutaneous melanin density at the upper inner arm is a strong predictor of risk of skin cancer.
Asunto(s)
Carcinoma Basocelular/patología , Carcinoma de Células Escamosas/patología , Melaninas/análisis , Melanoma/patología , Neoplasias Cutáneas/patología , Población Blanca , Adulto , Australia/epidemiología , Carcinoma Basocelular/epidemiología , Carcinoma de Células Escamosas/epidemiología , Estudios de Casos y Controles , Femenino , Humanos , Modelos Logísticos , Masculino , Melanoma/epidemiología , Persona de Mediana Edad , Fenotipo , Valor Predictivo de las Pruebas , Sistema de Registros , Factores de Riesgo , Factores Sexuales , Neoplasias Cutáneas/epidemiología , Espectrofotometría , Estadísticas no ParamétricasRESUMEN
The authors quantified improvement in predicting cutaneous malignant melanoma, basal cell carcinoma, and squamous cell carcinoma of the skin made possible by information on common variants of the melanocortin-1 receptor gene (MC1R) in a 1998-1999 population-based case-control study of subjects aged 20-59 years of northern European ancestry in Tasmania, Australia. Melanin density at the upper inner arm was estimated by spectrophotometry. DNA samples were genotyped for five MC1R variants: Val60Leu, Asp84Glu, Arg151Cys, Arg160Trp, and Asp294His. Among controls (n = 267), variant carriers, versus noncarriers, had lower (p < 0.01) mean melanin concentrations. Increased risk conferred by genotype was restricted mainly to those with the darkest skins: for subjects with at least 2% melanin, the odds of carrying each additional variant were higher for cutaneous malignant melanoma (n = 39; odds ratio = 1.45, 95% confidence interval: 0.87, 2.44), basal cell carcinoma (n = 35; odds ratio = 1.86, 95% confidence interval: 1.14, 3.02), and squamous cell carcinoma (n = 42; odds ratio = 2.67, 95% confidence interval: 1.50, 4.74) cases than for controls (n = 135). Adding MC1R information to prediction based on age, sex, and cutaneous melanin increased the area under the receiver operating characteristic curve by 1.4% (cutaneous malignant melanoma), 3.2% (basal cell carcinoma), or 2.0% (squamous cell carcinoma). The improvement in prediction was probably too small to be valuable in a clinical setting.
Asunto(s)
Carcinoma Basocelular/genética , Carcinoma de Células Escamosas/genética , Predisposición Genética a la Enfermedad/genética , Pruebas Genéticas/métodos , Genotipo , Melanoma/genética , Receptor de Melanocortina Tipo 1/genética , Neoplasias Cutáneas/genética , Adulto , Carcinoma Basocelular/epidemiología , Carcinoma de Células Escamosas/epidemiología , Estudios de Casos y Controles , Femenino , Frecuencia de los Genes , Predisposición Genética a la Enfermedad/epidemiología , Pruebas Genéticas/normas , Variación Genética/genética , Humanos , Masculino , Melaninas/análisis , Melanoma/epidemiología , Persona de Mediana Edad , Vigilancia de la Población/métodos , Valor Predictivo de las Pruebas , Curva ROC , Sistema de Registros , Medición de Riesgo/métodos , Factores de Riesgo , Piel/química , Neoplasias Cutáneas/epidemiología , Espectrofotometría/métodos , Espectrofotometría/normas , Tasmania/epidemiologíaRESUMEN
Nance-Horan syndrome (NHS) is an X-linked disorder characterized by congenital cataracts, dental anomalies, dysmorphic features, and, in some cases, mental retardation. NHS has been mapped to a 1.3-Mb interval on Xp22.13. We have confirmed the same localization in the original, extended Australian family with NHS and have identified protein-truncating mutations in a novel gene, which we have called "NHS," in five families. The NHS gene encompasses approximately 650 kb of genomic DNA, coding for a 1,630-amino acid putative nuclear protein. NHS orthologs were found in other vertebrates, but no sequence similarity to known genes was identified. The murine developmental expression profile of the NHS gene was studied using in situ hybridization and a mouse line containing a lacZ reporter-gene insertion in the Nhs locus. We found a complex pattern of temporally and spatially regulated expression, which, together with the pleiotropic features of NHS, suggests that this gene has key functions in the regulation of eye, tooth, brain, and craniofacial development.