Investigation of albinism genes in congenital esotropia.

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.

Confirmation of the adult-onset primary open angle glaucoma locus GLC1B at 2cen-q13 in an Australian family.

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.

A cross sectional study of the association between sex, smoking, and other lifestyle factors and osteoarthritis of the hand.

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.

Cutaneous melanin density of Caucasians measured by spectrophotometry and risk of malignant melanoma, basal cell carcinoma, and squamous cell carcinoma of the skin.

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.

Does the addition of information on genotype improve prediction of the risk of melanoma and nonmelanoma skin cancer beyond that obtained from skin phenotype?

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.

Mutations in a novel gene, NHS, cause the pleiotropic effects of Nance-Horan syndrome, including severe congenital cataract, dental anomalies, and mental retardation.

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.