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41.
Cloning of the essential myotonic dystrophy region and mapping of the putative defect. 总被引:56,自引:0,他引:56
C Aslanidis G Jansen C Amemiya G Shutler M Mahadevan C Tsilfidis C Chen J Alleman N G Wormskamp M Vooijs 《Nature》1992,355(6360):548-551
Myotonic dystrophy is a common dominant disorder (global incidence of 1:8,000) with variable onset and a protean nature of symptoms mainly involving progressive muscle wasting, myotonia and cataracts. To define the molecular defect, we have cloned the essential region of chromosome 19q13.3, including proximal and distal markers in a 700-kilobase contig formed by overlapping cosmids and yeast artificial chromosomes (YACs). The central part of the contig bridges an area of about 350 kilobases between two new flanking crossover borders. This segment has been extensively characterized through the isolation of five YAC clones and the subsequent subcloning in cosmids from which a detailed EcoRI, HindIII, MluI and NotI restriction map has been derived. Two genomic probes and two homologous complementary DNA probes were isolated using the cosmids. These probes are all situated within approximately 10 kilobases of genomic DNA and detect an unstable genomic segment in myotonic dystrophy patients. The length variation in this segment shows similarities to the instability seen at the fragile X locus. The physical map location and the genetic characteristics of the length polymorphism is compatible with a direct role in the pathogenesis of myotonic dystrophy. 相似文献
42.
F K Jansen H Müntefering K Schmidt 《Comptes rendus des séances de l'Académie des sciences. Série D, Sciences naturelles》1977,284(13):1235-1237
Normal DBA2 mice become highly diabetic after infection with the EMC virus. But 500 R X-irradiation before infection inhibits the increase of mean blood glucose levels thus indicating the participation of immune reactions in the appearance of diabetes. 相似文献
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Mutations in UBQLN2 cause dominant X-linked juvenile and adult-onset ALS and ALS/dementia 总被引:1,自引:0,他引:1
Deng HX Chen W Hong ST Boycott KM Gorrie GH Siddique N Yang Y Fecto F Shi Y Zhai H Jiang H Hirano M Rampersaud E Jansen GH Donkervoort S Bigio EH Brooks BR Ajroud K Sufit RL Haines JL Mugnaini E Pericak-Vance MA Siddique T 《Nature》2011,477(7363):211-215
Amyotrophic lateral sclerosis (ALS) is a paralytic and usually fatal disorder caused by motor-neuron degeneration in the brain and spinal cord. Most cases of ALS are sporadic but about 5-10% are familial. Mutations in superoxide dismutase 1 (SOD1), TAR DNA-binding protein (TARDBP, also known as TDP43) and fused in sarcoma (FUS, also known as translocated in liposarcoma (TLS)) account for approximately 30% of classic familial ALS. Mutations in several other genes have also been reported as rare causes of ALS or ALS-like syndromes. The causes of the remaining cases of familial ALS and of the vast majority of sporadic ALS are unknown. Despite extensive studies of previously identified ALS-causing genes, the pathogenic mechanism underlying motor-neuron degeneration in ALS remains largely obscure. Dementia, usually of the frontotemporal lobar type, may occur in some ALS cases. It is unclear whether ALS and dementia share common aetiology and pathogenesis in ALS/dementia. Here we show that mutations in UBQLN2, which encodes the ubiquitin-like protein ubiquilin?2, cause dominantly inherited, chromosome-X-linked ALS and ALS/dementia. We describe novel ubiquilin?2 pathology in the spinal cords of ALS cases and in the brains of ALS/dementia cases with or without UBQLN2 mutations. Ubiquilin?2 is a member of the ubiquilin family, which regulates the degradation of ubiquitinated proteins. Functional analysis showed that mutations in UBQLN2 lead to an impairment of protein degradation. Therefore, our findings link abnormalities in ubiquilin?2 to defects in the protein degradation pathway, abnormal protein aggregation and neurodegeneration, indicating a common pathogenic mechanism that can be exploited for therapeutic intervention. 相似文献
47.
Complex dynamics are often shown by simple ecological models and have been clearly demonstrated in laboratory and natural systems. Yet many classes of theoretically possible dynamics are still poorly documented in nature. Here we study long-term time-series data of a midge, Tanytarsus gracilentus (Diptera: Chironomidae), in Lake Myvatn, Iceland. The midge undergoes density fluctuations of almost six orders of magnitude. Rather than regular cycles, however, these fluctuations have irregular periods of 4-7 years, indicating complex dynamics. We fit three consumer-resource models capable of qualitatively distinct dynamics to the data. Of these, the best-fitting model shows alternative dynamical states in the absence of environmental variability; depending on the initial midge densities, the model shows either fluctuations around a fixed point or high-amplitude cycles. This explains the observed complex population dynamics: high-amplitude but irregular fluctuations occur because stochastic variability causes the dynamics to switch between domains of attraction to the alternative states. In the model, the amplitude of fluctuations depends strongly on minute resource subsidies into the midge habitat. These resource subsidies may be sensitive to human-caused changes in the hydrology of the lake, with human impacts such as dredging leading to higher-amplitude fluctuations. Tanytarsus gracilentus is a key component of the Myvatn ecosystem, representing two-thirds of the secondary productivity of the lake and providing vital food resources to fish and to breeding bird populations. Therefore the high-amplitude, irregular fluctuations in midge densities generated by alternative dynamical states dominate much of the ecology of the lake. 相似文献
48.
This paper deals with the FEEDBACK VERTEX SET problem on undirected graphs, which asks for the existence of a vertex set of bounded size that intersects all cycles. Due it is theoretical and practical importance,the problem has been the subject of intensive study. Motivated by the parameter ecology program we attempt to classify the parameterized and kernelization complexity of FEEDBACK VERTEX SET for a wide range of parameters.We survey known results and present several new complexity classifications. For example, we prove that FEEDBACK VERTEX SET is fixed-parameter tractable parameterized by the vertex-deletion distance to a chordal graph. We also prove that the problem admits a polynomial kernel when parameterized by the vertex-deletion distance to a pseudo forest, a graph in which every connected component has at most one cycle. In contrast, we prove that a slightly smaller parameterization does not allow for a polynomial kernel unless NP coNP=poly and the polynomial-time hierarchy collapses. 相似文献
49.
Germline mutations in PRKCSH are associated with autosomal dominant polycystic liver disease 总被引:7,自引:0,他引:7
Polycystic liver disease (PCLD, OMIM 174050) is a dominantly inherited condition characterized by the presence of multiple liver cysts of biliary epithelial origin. Fine mapping established linkage to marker D19S581 (Z(max) = 9.65; theta = 0.01) in four large Dutch families with PCLD. We identified a splice-acceptor site mutation (1138-2A-->G) in PRKCSH in three families, and a splice-donor site mutation (292+1G-->C) in PRKCSH segregated completely with PCLD in another family. The protein encoded by PRKCSH, here named hepatocystin, is predicted to localize to the endoplasmic reticulum. These findings establish germline mutations in PRKCSH as the probable cause of PCLD. 相似文献