A strong candidate for the 17q-linked BRCA1 gene, which influences susceptibility to breast and ovarian cancer, has been identified by positional cloning methods. Probable predisposing mutations have been detected in five of eight kindreds presumed to segregate BRCA1 susceptibility alleles. The mutations include an 11-base pair deletion, a 1-base pair insertion, a stop codon, a missense substitution, and an inferred regulatory mutation. The BRCA1 gene is expressed in numerous tissues, including breast and ovary, and encodes a predicted protein of 1863 amino acids. This protein contains a zinc finger domain in its amino-terminal region, but is otherwise unrelated to previously described proteins. Identification of BRCA1 should facilitate early diagnosis of breast and ovarian cancer susceptibility in some individuals as well as a better understanding of breast cancer biology.
Mitogen-activated protein kinases function in signal transduction pathways that are involved in controlling key cellular processes in many organisms. A mammalian member of this kinase family, MKK4/JNKK1/SEK1, has been reported to link upstream MEKK1 to downstream stress-activated protein kinase/JNK1 and p38 mitogen-activated protein kinase. This mitogen-activated protein kinase pathway has been implicated in the signal transduction of cytokine- and stress-induced apoptosis in a variety of cell types. Here, we report that two human tumor cell lines, derived from pancreatic carcinoma and lung carcinoma, harbor homozygous deletions that eliminate coding portions of the MKK4 locus at 17p, located approximately 10 cM centromeric of p53. In addition, in a set of 88 human cancer cell lines prescreened for loss of heterozygosity, we detected two nonsense and three missense sequence variants of MKK4 in cancer cell lines derived from human pancreatic, breast, colon, and testis cells. In vitro biochemical assays revealed that, when stimulated by MEKK1, four of the five altered MKK4 proteins lacked the ability to phosphorylate stress-activated protein kinase. Thus, the incidence of coding mutations of MKK4 in the set of cell lines is 6 of 213 (approximately 3%). These findings suggest that MKK4 may function as a suppressor of tumorigenesis or metastasis in certain types of cells.
Journal Article Histocompatibility Leukocyte Antigens in Patients with Toxic-Shock Syndrome Get access Robert H. Latham, Robert H. Latham Field Services Division Epidemiology Program Office Centers for Disease Control Search for other works by this author on: Oxford Academic PubMed Google Scholar Bryon T. Haslam, Bryon T. Haslam Utah State Department of Health Search for other works by this author on: Oxford Academic PubMed Google Scholar Charles Dewitt, Charles Dewitt University of Utah College of Medicine, Salt Lake City, Utah Search for other works by this author on: Oxford Academic PubMed Google Scholar Mark Skolnick, Mark Skolnick University of Utah College of Medicine, Salt Lake City, Utah Search for other works by this author on: Oxford Academic PubMed Google Scholar Charles B. Smith Charles B. Smith University of Utah College of Medicine, Salt Lake City, Utah Search for other works by this author on: Oxford Academic PubMed Google Scholar The Journal of Infectious Diseases, Volume 147, Issue 4, April 1983, Page 783, https://doi.org/10.1093/infdis/147.4.783 Published: 01 April 1983
Abstract Linkage analyses between 21 genetic markers including HLA‐A, B, and the postulated locus for determining total serum IgE levels were done to try to clarify the inheritance of total IgE levels and to map the locus. A total of 316 individuals from five Mormon kindreds were studied, and data from an additional 204 Amish individuals from 11 families were analyzed for possible HLA linkage. Segregation analyses of both data sets did not give clear definition of the mode of inheritance of total IgE levels, but purely environmental models were rejected. Linkage analyses gave significant evidence against HLA linkage with the codominant, recessive, or dominant model of inheritance for total IgE levels. No significant evidence for linkage with any of the genetic markers was obtained. Since total serum IgE levels are correlated with allergies, understanding the genetics of total IgE levels is important to understanding the genetics of allergic disease in man.
The calculation of probabilities on pedigrees of arbitrary complexity is discussed for a basic model of transmission and penetrance (encompassing Mendelian inheritance, and certain environmental influences). The structure of pedigrees, and the types of loops occurring, is discussed. Some results in graph theory are obtained and, using these, a recurrence relation derived for certain probabilities. The recursive procedure enables the successive peeling off of certain members of the pedigree, and the condensation of the information on those individuals into a function on a subset of those remaining. The underlying theory is set out, and examples given of the utilization of the resulting algorithm.
