PubMed · 1537658
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M L McHam, A Fulton. 1992. Albinism.. https://doi.org/10.1097/00004397-199203210-00015
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We apply a method proposed by Rogatko et al. [1995: Am J Med Genet 59:24-32] to estimate carrier risks using genetic linkage data. The method is illustrated for X-linked ocular albinism. Linkage data from pedigrees were combined with genome mapping data to compute carrier risks for individuals with unknown carrier status based on pedigree data alone. We considered two situations. First, a linkage map with some ambiguity in the gene order was considered. This analysis allows us to examine the effect of incomplete genetic map information on risk computations. Second, published physical and meiotic mapping information was used to derive a linkage map that could be assumed known without ambiguity. In both situations, the mean and median estimate of carrier risk differed significantly from that obtained using pedigree relationships only, in that the computed risk was significantly different from the a priori value of 0.5. The 95% CI's associated with point estimates of risk made using the known map or an map with ambiguity did not overlap in some cases. These results suggest that the risk estimate and the confidence with which a risk estimate can be imparted may depend on the genetic map and marker data used in the risk estimation procedure. We conclude that the method presented here can be used to estimate genetic risk under a variety of analytical conditions.
The factors that regulate normal retinal development remain obscure. However, it is known that elements in the retinal pigment epithelium are critical. When melanin is absent there is a reduction in rods, the central retina fails to develop fully and there is a systematic distortion in the chiasmatic projection to the brain. It has been demonstrated using transgenic mice that the chiasmatic abnormality is controlled by the tyrosinase gene, which is the key enzyme in melanin synthesis. Here we examine whether the two retinal deficits are regulated by this gene. We have examined the distribution of photoreceptors in an albino mouse strain in which a functional tyrosinase gene has been inserted and compared these transgenics with albino and wild type mice. In albinos, rod photoreceptors were reduced by approximately 30%, but were normal in the transgenics. Cone numbers were unchanged. Cell density in the ganglion cell layer was examined in transgenic rabbits, in which albinism had also been rescued with the tyrosinase gene. Normal rabbits have a steep gradient in cell density between central and peripheral retina. Cell density was abnormally low in the central retina in albinos, but normal in the transgenics. Hence, the tyrosinase gene is responsible for each of the retinal deficits associated with albinism. However, it is not clear whether this is due to the absence of melanin or whether the key agent is an associated cell product.
Waardenburg syndrome (WS) is a clinically and genetically heterogeneous disease accounting for >2% of the congenitally deaf population. It is characterized by deafness in association with pigmentary anomalies and various defects of neural crest-derived tissues. At least four types are recognized (WS1, WS2, WS3 and WS4) on the basis of clinical and genetic criteria. Two previously described families seemed to delineate a new subtype characterized by WS2 in conjunction with ocular albinism (OA). Since mutations in the MITF gene are responsible for some instances of WS2, we screened for mutations in one of the WS2-OA families and discovered a 1 bp deletion in exon 8 of MITF. OA previously has been associated with compound heterozygosity for a mutant TYR allele and the TYR(R402Q) allele, a functionally significant polymorphism that is associated with moderately reduced tyrosinase catalytic activity. In this family, all of the individuals with the OA phenotype are either homozygous or heterozygous for TYR(R402Q), and heterozyous for the 1 bp deletion in MITF This suggests that the WS2-OA phenotype may result from digenic interaction between a gene for a transcription factor (MITF) and a gene that it regulates (TYR).