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121.
The genetic basis of most conditions characterized by congenital contractures is largely unknown. Here we show that mutations in the embryonic myosin heavy chain (MYH3) gene cause Freeman-Sheldon syndrome (FSS), one of the most severe multiple congenital contracture (that is, arthrogryposis) syndromes, and nearly one-third of all cases of Sheldon-Hall syndrome (SHS), the most common distal arthrogryposis. FSS and SHS mutations affect different myosin residues, demonstrating that MYH3 genotype is predictive of phenotype. A structure-function analysis shows that nearly all of the MYH3 mutations are predicted to interfere with myosin's catalytic activity. These results add to the growing body of evidence showing that congenital contractures are a shared outcome of prenatal defects in myofiber force production. Elucidation of the genetic basis of these syndromes redefines congenital contractures as unique defects of the sarcomere and provides insights about what has heretofore been a poorly understood group of disorders. 相似文献
122.
Sayer JA Otto EA O'Toole JF Nurnberg G Kennedy MA Becker C Hennies HC Helou J Attanasio M Fausett BV Utsch B Khanna H Liu Y Drummond I Kawakami I Kusakabe T Tsuda M Ma L Lee H Larson RG Allen SJ Wilkinson CJ Nigg EA Shou C Lillo C Williams DS Hoppe B Kemper MJ Neuhaus T Parisi MA Glass IA Petry M Kispert A Gloy J Ganner A Walz G Zhu X Goldman D Nurnberg P Swaroop A Leroux MR Hildebrandt F 《Nature genetics》2006,38(6):674-681
123.
Truncating mutations in the Fanconi anemia J gene BRIP1 are low-penetrance breast cancer susceptibility alleles 总被引:21,自引:0,他引:21
Seal S Thompson D Renwick A Elliott A Kelly P Barfoot R Chagtai T Jayatilake H Ahmed M Spanova K North B McGuffog L Evans DG Eccles D;Breast Cancer Susceptibility Collaboration 《Nature genetics》2006,38(11):1239-1241
We identified constitutional truncating mutations of the BRCA1-interacting helicase BRIP1 in 9/1,212 individuals with breast cancer from BRCA1/BRCA2 mutation-negative families but in only 2/2,081 controls (P = 0.0030), and we estimate that BRIP1 mutations confer a relative risk of breast cancer of 2.0 (95% confidence interval = 1.2-3.2, P = 0.012). Biallelic BRIP1 mutations were recently shown to cause Fanconi anemia complementation group J. Thus, inactivating truncating mutations of BRIP1, similar to those in BRCA2, cause Fanconi anemia in biallelic carriers and confer susceptibility to breast cancer in monoallelic carriers. 相似文献
124.
Richardson RJ Dixon J Malhotra S Hardman MJ Knowles L Boot-Handford RP Shore P Whitmarsh A Dixon MJ 《Nature genetics》2006,38(11):1329-1334
The epidermis is a highly organized structure, the integrity of which is central to the protection of an organism. Development and subsequent maintenance of this tissue depends critically on the intricate balance between proliferation and differentiation of a resident stem cell population; however, the signals controlling the proliferation-differentiation switch in vivo remain elusive. Here, we show that mice carrying a homozygous missense mutation in interferon regulatory factor 6 (Irf6), the homolog of the gene mutated in the human congenital disorders Van der Woude syndrome and popliteal pterygium syndrome, have a hyperproliferative epidermis that fails to undergo terminal differentiation, resulting in soft tissue fusions. We further demonstrate that mice that are compound heterozygotes for mutations in Irf6 and the gene encoding the cell cycle regulator protein stratifin (Sfn; also known as 14-3-3sigma) show similar defects of keratinizing epithelia. Our results indicate that Irf6 is a key determinant of the keratinocyte proliferation-differentiation switch and that Irf6 and Sfn interact genetically in this process. 相似文献
125.
We describe habitat characteristics of 8 small mammal species occurring in the Manti-LaSal National Forest in southeastern Utah. Thirty-seven grids across 7 vegetation types were sample by live-trapping from May through October 1994 and 1995. Logistic regression models of habitat measurements correctly classified small mammal presence 36%-87% of the time. Except for 1 instance, 4 Peromyscus species present in a specific vegetation type were negatively associated with forb or grass cover. Microtus montanus was present primarily on mesas and was positively associated with tall tree and low shrub cover. Neotoma mexicana was present only in canyons and was found primarily in the pinyon-juniper ( Pinus edulis-Juniperus osteosperma ) vegetation type. Tamias spp. was present in all vegetation types. Our results allow better management of these species by providing greater understanding of their use of habitat within vegetation types. 相似文献
126.
Since Euro-American settlement, fire exclusion and other factors have dramatically altered interior western coniferous forests. Once open and parklike, present-day structure in many southwestern Pinus ponderosa forests consists of dense stands of young, small-diameter trees, with small patches of larger, old trees, and relict open bunchgrass areas. Our objectives were to assess differences in soil properties associated with these different vegetation patches. We examined soil morphological characteristics, pH, organic C concentration, total N concentration, C:N ratio, and phytolith concentration from profiles within 6 transects (18 soil pedons) crossing patches of dense stands of small diameter trees, patches of old-growth trees, and open grassy areas. Results indicate that old-growth plots had significantly lower A horizon pH and thicker O horizons than grass plots. In general, we found vegetation patches had statistically similar C and N concentrations and C:N ratios for A and B horizons; however, C in the A horizon was positively correlated with O horizon accumulation ( r 2 = 0.79). Greater accumulation of organic C in the A horizon of forested areas contrasts with commonly reported results from mesic, mid-continental prairie-forest ecosystems but is typical for many arid, semiarid, and humid savanna ecosystems. Phytolith concentration was similar among old-growth pine, dense younger pine, and open grassy plots; the lack of a spatial pattern in phytolith distribution could indicate that grass cover was more spatially continuous in the past. Additionally, this interpretation is consistent with current theories regarding historical vegetation change in these forests. 相似文献
127.
Irina Tikhonenko Valentin Magidson Ralph Gräf Alexey Khodjakov Michael P. Koonce 《Cellular and molecular life sciences : CMLS》2013,70(7):1285-1296
The M-type kinesin isoform, Kif9, has recently been implicated in maintaining a physical connection between the centrosome and nucleus in Dictyostelium discoideum. However, the mechanism by which Kif9 functions to link these two organelles remains obscure. Here we demonstrate that the Kif9 protein is localized to the nuclear envelope and is concentrated in the region underlying the centrosome point of attachment. Nuclear anchorage appears mediated through a specialized transmembrane domain located in the carboxyl terminus. Kif9 interacts with microtubules in in vitro binding assays and effects an endwise depolymerization of the polymer. These results suggest a model whereby Kif9 is anchored to the nucleus and generates a pulling force that reels the centrosome up against the nucleus. This is a novel activity for a kinesin motor, one important for progression of cells into mitosis and to ensure centrosome-nuclear parity in a multinuclear environment. 相似文献
128.
Michael R. Yeaman 《Cellular and molecular life sciences : CMLS》2010,67(4):525-544
Platelets interact with bacterial pathogens through a wide array of cellular and molecular mechanisms. The consequences of
this interaction may significantly influence the balance between infection and immunity. On the one hand, recent data indicate
that certain bacteria may be capable of exploiting these interactions to gain a virulence advantage. Indeed, certain bacterial
pathogens appear to have evolved specific ways in which to subvert activated platelets. Hence, it is conceivable that some
bacterial pathogens exploit platelet responses. On the other hand, platelets are now known to possess unambiguous structures
and functions of host defense effector cells. Recent discoveries emphasize critical features enabling such functions, including
expression of toll-like receptors that detect hallmark signals of bacterial infection, an array of microbicidal peptides,
as well as other host defense molecules and functions. These concepts are consistent with increased risk and severity of bacterial
infection as correlates of clinical abnormalities in platelet quantity and quality. In these respects, the molecular and cellular
roles of platelets in host defense against bacterial pathogens are explored with attention on advances in platelet immunobiology. 相似文献
129.
130.
Karina Weinhold Udo Krause-Buchholz Gerhard Rödel Michael Kasper Kathrin Barth 《Cellular and molecular life sciences : CMLS》2010,67(15):2631-2642
P2X4 and P2X7 receptors are ATP-gated ion channels that are co-expressed in alveolar epithelial type I cells. Both receptors
are localized to the plasma membrane and partly associated with lipid rafts. Here we report on our study in an alveolar epithelial
cell line of the molecular organization of P2X7R and P2X4R receptors and the effect of their knockdown. Native gel electrophoresis
reveals three P2X7R complexes of ~430, ~580 and ~760 kDa. The latter two correspond exactly in size to signals of Cav-1, the
structural protein of caveolae. Interestingly knockdown of P2rx7 affects protein levels, the intracellular distribution and the supramolecular organization of Cav-1 as well as of P2X4R,
which is mainly detected in a complex of ~430 kDa. Our data suggest upregulation of P2X4R as a compensatory mechanism of P2X7R
depletion. 相似文献