American journal of human genetics
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Lymphangiomyomatosis (LAM) is a rare disease, of unknown etiology, affecting women almost exclusively. Lung transplantation is the only consistently effective therapy for LAM. Microscopically, LAM consists of a diffuse proliferation of smooth muscle cells. ⋯ Our findings indicate that the TSC2 gene may be involved in the pathogenesis of sporadic LAM. However, genetic transmission of LAM has not been reported. Women with LAM may have low-penetrance germ-line TSC2 mutations, or they may be mosaic, with TSC2 mutations in the lung and the kidney but not in other organs.
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Malignant hyperthermia (MH) is a pharmacogenetic disorder of skeletal muscle that is triggered in genetically predisposed individuals by common anesthetics and muscle relaxants. The ryanodine receptor (RYR1) is mutated in a number of MH pedigrees, some members of which also have central core disease (CCD), an inherited myopathy closely associated with MH. Mutation screening of 6 kb of the RYR1 gene has identified four adjacent novel mutations, C6487T, G6488A, G6502A, and C6617T, which result in the amino acid alterations Arg2163Cys, Arg2163His, Val2168Met, and Thr2206Met, respectively. ⋯ Correlation analysis of the in vitro contracture-test data available for pedigrees bearing these and other RYR1 mutations showed an exceptionally good correlation between caffeine threshold and tension values, whereas no correlation was observed between halothane threshold and tension values. This finding has important ramifications for assignment of the MH-susceptible phenotype, in genotyping studies, and indicates that assessment of recombinant individuals on the basis of caffeine response is justified, whereas assessment on the basis of halothane response may be problematic. Interestingly, the data suggest a link between the caffeine threshold and tension values and the MH/CCD phenotype.
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PTEN, a protein tyrosine phosphatase with homology to tensin, is a tumor-suppressor gene on chromosome 10q23. Somatic mutations in PTEN occur in multiple tumors, most markedly glioblastomas. Germ-line mutations in PTEN are responsible for Cowden disease (CD), a rare autosomal dominant multiple-hamartoma syndrome. ⋯ Loss of PTEN expression was an early event, reflected in loss of the wild-type allele in DNA from normal tissue adjacent to the breast and thyroid tumors. In RNA from normal tissues from three families, mutant transcripts appeared unstable. Germ-line PTEN mutations predispose to breast cancer in association with CD, although the signs of CD may be subtle.