共查询到20条相似文献,搜索用时 15 毫秒
1.
J Melki S Abdelhak P Sheth M F Bachelot P Burlet A Marcadet J Aicardi A Barois J P Carriere M Fardeau 《Nature》1990,344(6268):767-768
Proximal spinal muscular atrophies represent the second most common fatal, autosomal recessive disorder after cystic fibrosis. The childhood form is classically subdivided into three groups: acute Werdnig-Hoffmann (type I), intermediate Werdnig-Hoffmann disease (type II) and Kugelberg-Welander disease (type III). These different clinical forms have previously been attributed to either genetic heterogeneity or variable expression of different mutations at the same locus. Research has been hindered because the underlying biochemical defect is unknown, and there are insufficient large pedigrees with the most common and severe form (type I) available for study. Therefore, we have undertaken a genetic linkage analysis of the chronic forms of the disease (types II and III) as an initial step towards the ultimate goal of characterizing the gene(s) responsible for all three types. We report here the assignment of the locus for the chronic forms to the long arm of chromosome 5 (5q12-q14), with the anonymous DNA marker D5S39, in 24 multiplex families of distinct ethnic origin. Furthermore, no evidence for genetic heterogeneity was found for types II and III in our study, suggesting that these two forms are allelic disorders. 相似文献
2.
T C Gilliam L M Brzustowicz L H Castilla T Lehner G K Penchaszadeh R J Daniels B C Byth J Knowles J E Hislop Y Shapira 《Nature》1990,345(6278):823-825
The childhood-onset spinal muscular atrophies (SMAs) describe a heterogeneous group of disorders that selectively affect the alpha motoneuron. We have shown that chronic childhood-onset SMA (SMA II and III) maps to a single locus on chromosome 5q. Acute SMA (SMA Type I/Werdnig-Hoffmann/severe/infantile) is the main cause of heritable infant mortality. Mapping the acute SMA locus by conventional methods is complicated by the rapidly fatal course of the disease and its recessive mode of inheritance. We present here the typing of four inbred acute-SMA families with DNA markers on chromosome 5q and analysis of these together with acute families from our previous study to demonstrate genetic homogeneity between the acute and chronic forms of SMA. The data indicate that the acute SMA locus maps to chromosome 5q11.2-13.3. Two families seem unlinked to 5q markers, raising the possibility of genetic heterogeneity or disease misclassification within the acute and chronic family sets. 相似文献
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4.
Localization of an ataxia-telangiectasia gene to chromosome 11q22-23 总被引:52,自引:0,他引:52
R A Gatti I Berkel E Boder G Braedt P Charmley P Concannon F Ersoy T Foroud N G Jaspers K Lange 《Nature》1988,336(6199):577-580
Ataxia-telangiectasia (AT) is a human autosomal recessive disorder of childhood characterized by: (1) progressive cerebellar ataxia with degeneration of Purkinje cells; (2) hypersensitivity of fibroblasts and lymphocytes to ionizing radiation; (3) a 61-fold and 184-fold increased cancer incidence in white and black patients, respectively; (4) non-random chromosomal rearrangements in lymphocytes; (5) thymic hypoplasia with cellular and humoral (IgA and IgG2) immunodeficiencies; (6) elevated serum level of alphafetoprotein; (7) premature ageing; and (8) endocrine disorders, such as insulin-resistant diabetes mellitus. A DNA processing or repair protein is the suspected common denominator in this pathology. Heterozygotes are generally healthy; however, the sensitivity of their cultured cells to ionizing radiation is intermediate between normal individuals and that of affected homozygotes. Furthermore, heterozygous females are at an increased risk of breast cancer. These findings, when coupled with an estimated carrier frequency of 0.5-5.0%, suggest that (1) as many as one in five women with breast cancer may carry the AT gene and that (2) the increased radiation sensitivity of AT heterozygotes may be causing radiation therapists to reduce the doses of radiation used for treating cancer in all patients. To identify the genetic defect responsible for this multifaceted disorder, and to provide effective carrier detection, we performed a genetic linkage analysis of 31 families with AT-affected members. This has allowed us to localize a gene for AT to chromosomal region 11q22-23. 相似文献
5.
The mapping of a cDNA from the human X-linked Duchenne muscular dystrophy gene to the mouse X chromosome 总被引:2,自引:0,他引:2
N Brockdorff G S Cross J S Cavanna E M Fisher M F Lyon K E Davies S D Brown 《Nature》1987,328(6126):166-168
The recent discovery of sequences at the site of the Duchenne muscular dystrophy (DMD) gene in humans has opened up the possibility of a detailed molecular analysis of the genes in humans and in related mammalian species. Until relatively recently, there was no obvious mouse model of this genetic disease for the development of therapeutic strategies. The identification of a mouse X-linked mutant showing muscular dystrophy, mdx, has provided a candidate mouse genetic homologue to the DMD locus; the relatively mild pathological features of mdx suggest it may have more in common with mutations of the Becker muscular dystrophy type at the same human locus, however. But the close genetic linkage of mdx to G6PD and Hprt on the mouse X chromosome, coupled with its comparatively mild pathology, have suggested that the mdx mutation may instead correspond to Emery Dreifuss muscular dystrophy which itself is closely linked to DNA markers at Xq28-qter in the region of G6PD on the human X chromosome. Using an interspecific mouse domesticus/spretus cross, segregating for a variety of markers on the mouse X chromosome, we have positioned on the mouse X chromosome sequences homologous to a DMD cDNA clone. These sequences map provocatively close to the mdx mutation and unexpectedly distant from sparse fur, spf, the mouse homologue of OTC (ornithine transcarbamylase) which is closely linked to DMD on the human X chromosome. 相似文献
6.
Recent work suggests that an autosomal dominant gene for schizophrenia may be located on the 5q11-q13 region of chromosome 5 (refs 1 and 2): a report of schizophrenia associated with trisomy 5q11-q13 in two members of a family of Chinese origin prompted the discovery of linkage with markers p105-599Ha and p105-153Ra in five Icelandic and two English schizophrenic families. The strongest linkage was observed when the phenotype was broadly defined to include minor psychiatric diagnoses not traditionally considered part of the schizophrenia spectrum. By contrast, no evidence was found of linkage in a single multiplex Swedish schizophrenic pedigree. To determine whether these conflicting results arise from genetic and/or uncertainties in defining the schizophrenic phenotype, we examined fifteen Scottish schizophrenic families with restriction fragment length polymorphisms that span this region. We found no evidence for linkage, regardless of how broadly or narrowly the schizophrenic phenotype is defined, and conclude that a susceptibility locus, whose presence awaits confirmation, on the proximal portion of the long arm of chromosome 5 can be responsible for only a minority of cases of familial schizophrenia. 相似文献
7.
Spinal muscular atrophy (SMA) is a motor neuron disease and the leading genetic cause of infant mortality; it results from loss-of-function mutations in the survival motor neuron 1 (SMN1) gene. Humans have a paralogue, SMN2, whose exon 7 is predominantly skipped, but the limited amount of functional, full-length SMN protein expressed from SMN2 cannot fully compensate for a lack of SMN1. SMN is important for the biogenesis of spliceosomal small nuclear ribonucleoprotein particles, but downstream splicing targets involved in pathogenesis remain elusive. There is no effective SMA treatment, but SMN restoration in spinal cord motor neurons is thought to be necessary and sufficient. Non-central nervous system (CNS) pathologies, including cardiovascular defects, were recently reported in severe SMA mouse models and patients, reflecting autonomic dysfunction or direct effects in cardiac tissues. Here we compared systemic versus CNS restoration of SMN in a severe mouse model. We used an antisense oligonucleotide (ASO), ASO-10-27, that effectively corrects SMN2 splicing and restores SMN expression in motor neurons after intracerebroventricular injection. Systemic administration of ASO-10-27 to neonates robustly rescued severe SMA mice, much more effectively than intracerebroventricular administration; subcutaneous injections extended the median lifespan by 25 fold. Furthermore, neonatal SMA mice had decreased hepatic Igfals expression, leading to a pronounced reduction in circulating insulin-like growth factor 1 (IGF1), and ASO-10-27 treatment restored IGF1 to normal levels. These results suggest that the liver is important in SMA pathogenesis, underscoring the importance of SMN in peripheral tissues, and demonstrate the efficacy of a promising drug candidate. 相似文献
8.
Localization of the malignant hyperthermia susceptibility locus to human chromosome 19q12-13.2 总被引:19,自引:0,他引:19
T V McCarthy J M Healy J J Heffron M Lehane T Deufel F Lehmann-Horn M Farrall K Johnson 《Nature》1990,343(6258):562-564
Malignant hyperthermia (MH) is an inherited human skeletal muscle disorder and is one of the main causes of death due to anaesthesia. The reported incidence of MH varies from 1 in 12,000 in children to 1 in 40,000 in adults. MH is triggered in susceptible people by all commonly used inhalational anaesthetics; it is characterized by a profoundly accelerated muscle metabolism, contractures, hyperthermia and tachycardia. Susceptibility to MH (MHS) is predicted by contracture tests on muscle tissue obtained by biopsy. An almost identical disorder known as porcine MH exists in pigs. The genetics of the porcine syndrome have been extensively studied; the locus controlling expression of porcine MH is genetically linked to the glucose phosphate isomerase locus (GPI). In man, GPI has been mapped to the q12-13.2 region of chromosome 19 (refs 10-12). We have now investigated genetic linkage in several extended Irish pedigrees in which MHS is segregating as an autosomal dominant trait. Here we show linkage between MHS and DNA markers from the GPI region of human chromosome 19 with a maximum log likelihood ratio (lod score) of 5.65 at the CYP2A locus. These results indicate that human and porcine MH are most probably due to mutations in homologous genes, and also provide a potentially accurate and noninvasive method of diagnosis for MHS. 相似文献
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Exclusion of linkage to 5q11-13 in families with schizophrenia and other psychiatric disorders 总被引:2,自引:0,他引:2
S D Detera-Wadleigh L R Goldin R Sherrington I Encio C de Miguel W Berrettini H Gurling E S Gershon 《Nature》1989,340(6232):391-393
Recently a linkage study on five Icelandic and two English pedigrees has provided evidence for a dominant gene for schizophrenia on 5q11-13 (ref. 1). In that study, families with bipolar illness were not included. Using the same probes, two similar but independent investigations on one Swedish pedigree and on fifteen Scottish families excluded linkage to schizophrenia. To evaluate whether the susceptibility gene on 5q11-13 is a common cause of schizophrenia in other populations, we examined five affected North American pedigrees using probes to the D5S39, D5S76 and dihydrofolate reductase loci. Two families in the present series had cases of bipolar disorder. We found that linkage can be excluded by multipoint analysis. These results, taken together, suggest that the disease gene on 5q11-13 does not account for most cases of familial schizophrenia. 相似文献
11.
A novel family of human major histocompatibility complex-related genes not mapping to chromosome 6 总被引:18,自引:0,他引:18
Thymocyte antigens CD1 [Thy,gp45,12] are thought to be the human counterparts of mouse thymus leukaemia (TL) antigens. Serological and biochemical analyses indicate that at least three subsets exist, the first of which (HTA 1/T6) was initially identified by the monoclonal antibody NA1/34. Like TL, CD1 are expressed on cortical thymocytes as well as on some lymphoid neoplasias, and resemble in structure major histocompatibility complex (MHC) class I antigens. However HTA 1/T6 is loosely associated with beta 2-microglobulin and is also found linked by a disulphide bridge to CD8(T8). A molecular genetic approach is needed to investigate the CD1 system, to clarify its relationship to TL antigens and to understand its regulation. We report the isolation of complementary DNA (cDNA) clones encoding a CD1 antigen. These clones reveal a novel family of genes which are MHC-related but are neither equivalent to mouse TL antigens nor linked to the MHC. 相似文献
12.
Genetic linkage of Werner's syndrome to five markers on chromosome 8. 总被引:14,自引:0,他引:14
Werner's syndrome (WS) is a rare autosomal recessive disease in which the affected individuals display symptoms of premature ageing. The substantial phenotypic overlap between WS and normal ageing indicates that these two conditions may have pathogenetic mechanisms in common. The WS mutation has pleiotropic effects, and patients and their cells show many differences compared with normals. Despite extensive study of the clinical and biochemical features of this disorder, the primary genetic defect remains unknown. We have undertaken a genetic linkage study in an effort to identify the locus of the primary defect. Here we report close genetic linkage of the WS mutation to a group of markers on chromosome 8. 相似文献
13.
Localization of the region homologous to the Duchenne muscular dystrophy locus on the mouse X chromosome 总被引:1,自引:0,他引:1
Recent progress has resulted in part of the gene mutated in Duchenne and the milder Becker muscular dystrophies being cloned and has suggested that the gene itself extends over 1,000 to 2,000 kilobases (kb). To study how mutations in this gene affect muscle development and integrity, it would be of interest to have available a mouse model of the human disease. The mouse mdx mutation affects muscle and confers a mild dystrophic syndrome, but it is not clear whether this mutation is equivalent to Duchenne/Becker muscular dystrophy in man. Here we describe the use of two sequences from the human Duchenne muscular dystrophy (DMD) gene that cross-hybridize to mouse X-linked sequences to localize the gene homologous to DMD in the mouse. Both sequences map to the region of 10 centimorgan lying between the Tabby (Ta) and St14-1 (DxPas8) loci, close to the phosphorylase b kinase locus (Phk). By analogy with the human X-chromosome, we conclude that the region in the mouse around the G6pd and St14-1 loci may contain two genes corresponding to distinct human myopathies: Emery Dreifuss muscular dystrophy which is known to be closely linked to St14-1 in man and the DMD homologue described here. 相似文献
14.
Genetic linkage of bilateral acoustic neurofibromatosis to a DNA marker on chromosome 22 总被引:9,自引:0,他引:9
G A Rouleau W Wertelecki J L Haines W J Hobbs J A Trofatter B R Seizinger R L Martuza D W Superneau P M Conneally J F Gusella 《Nature》1987,329(6136):246-248
Bilateral acoustic neurofibromatosis (BANF) is a severe autosomal dominant disorder involving development of multiple tumours of the nervous system including meningiomas, gliomas, neurofibromas and particularly bilateral acoustic neuromas. We have used genetic linkage analysis with DNA markers to establish that the defective gene causing BANF is on chromosome 22, and is therefore distinct from the gene for the von Recklinghausen form of neurofibromatosis, which maps to chromosome 17. Linked DNA markers will be particularly valuable in BANF, facilitating early detection of tumours and thereby permitting more effective surgical intervention. In view of the reported loss of genes on chromosome 22 in meningiomas and acoustic neuromas, the genetic localization of the primary BANF defect strongly supports the concept that the disease locus encodes a 'tumour suppressor' gene. Isolation of this gene should provide insights into the pathogenesis of acoustic neuromas and other nervous system tumours, as well as into the control of proliferation and differentiation of neural crest cells. 相似文献
15.
为鉴定控制谷子抽穗的关键基因,通过甲基磺酸乙酯(ethyl methyl sulfonate,EMS)诱变谷子参考基因组测序品种豫谷1号,获得遗传稳定的谷子超早抽穗突变体jt1242-14b.与豫谷1号相比,jt1242-14b抽穗期明显提前,茎秆变细,叶片变窄、变短.遗传分析表明,突变性状受隐性单基因控制.以SSR41(父本)、jt1242-14b(母本)和F2群体进行突变基因定位,结果表明,该基因位于第9号染色体,在分子标记In4746和In9-11之间的4 447 kb之内.进一步测序比对分析发现突变位点位于PHYB基因内部,因此,PHYB很可能是该早熟突变体的目标基因.本研究为谷子早抽穗基因克隆及PHYB基因功能研究提供材料基础. 相似文献
16.
Identification and mapping to chromosome 1 of a susceptibility locus for periinsulitis in non-obese diabetic mice 总被引:11,自引:0,他引:11
Insulin-dependent diabetes mellitus (IDDM) is a polygenic disease caused by autoimmune destruction of insulin-producing beta cells in the islets of Langerhans. Its onset is preceded by a long and variable period in which lymphoid cells infiltrate the pancreas but first remain outside the islets (peri-insulitis) before invading them (insulitis). Among susceptibility loci, only the major histocompatibility complex (MHC) has been clearly assigned. Genetic study of the nonobese diabetic (NOD) mouse model for insulin-dependent diabetes mellitus has revealed genetic linkage of insulitis and of early onset diabetes with two non-MHC loci mapping to chromosome 3 and 11 respectively. Here we report a close association of periinsulitis with a third non-MHC locus mapping to chromosome 1. Successive stages in the progression of diabetic disease thus appear to be controlled by distinct genes or sets of genes. 相似文献
17.
将DNA单链构象多态(SSCP)检测的原理,应用于“显微切割的人染色体17q11—12探针池”批量分离单拷贝片段,取得了很好效果。从筛选出的74个次级单拷贝中有效地鉴定出37个非同源的单拷贝片段。这比传统的仅限于长度比较而确认的非同源单拷贝片段(12个)多出25个.其中部分已经DNA测序证实。结果提示:采用SSCP技术区分相似分子量单拷贝片段的同源性,可显著地提高从“显微切割探针池”分离和克隆非同源单拷贝片段的效率。本文还将一部分单拷贝片段作为探讨,与人基因组DNA的限制性片段作Southern印迹杂交,结果均只显示单一杂交带,说明单拷贝DNA片段的结论是可靠的。 相似文献
18.
多层螺旋CT在脊柱损伤诊断中的应用 总被引:5,自引:0,他引:5
目的:评价多层螺旋CT(MSCT)在脊柱损伤诊断中的应用价值。方法:对36例脊柱损伤患行多层螺旋CT扫描,利用Syngo 3D软件进行多平面重建(MPR)、表面遮盖显示(SSD)、最大密度投影(MIP)以及用:Fly-Through作仿真内窥镜观察,全方位对病变部位、范围、解剖结构及邻近组织关系进行比较分析。结果:全组病例的薄层重建及三维重建显示椎体骨折36例,椎体骨折伴椎管狭窄13例,小关节脱位12例。多层螺旋CT能很好地显示相应的骨折、脱位及椎管情况,尤其是MPR及MIP对椎体骨折显示率为100%;仿真内窥镜能多角度观察病变椎管内形态及狭窄状况。结论:多层螺旋四尤其是MPR、MIP及仿真内窥镜的应用能直观、立体、清晰、多角度地显示脊柱损伤.具有较高的临床应用价值。 相似文献
19.
Evidence against linkage of schizophrenia to markers on chromosome 5 in a northern Swedish pedigree 总被引:19,自引:0,他引:19
J L Kennedy L A Giuffra H W Moises L L Cavalli-Sforza A J Pakstis J R Kidd C M Castiglione B Sjogren L Wetterberg K K Kidd 《Nature》1988,336(6195):167-170
Schizophrenia is a severe mental illness with a typically chronic course affecting nearly 1% of the human population. It is generally accepted that genetic factors have an important pathogenic role in a substantial portion of schizophrenia cases; however, despite decades of family studies, there is no agreed-upon mode of inheritance. The discovery of genetic aetiologic factors and resolution of the inheritance pattern(s) will undoubtably emerge from genetic linkage studies. With these objectives in mind, we undertook a linkage project, starting in 1985, in a previously well-documented kindred from north Sweden. Multipoint linkage analyses were used to screen the proximal long arm of chromosome 5 using restriction fragment length polymorphism (RFLP) markers at five loci and the distal long arm using RFLPs at two loci, one of which was the locus for the glucocorticoid receptor. We found strong evidence against linkage between schizophrenia and the seven loci. These results, together with the positive evidence for linkage of schizophrenia with markers in the proximal long arm of chromosome 5 lead us to conclude that the genetic factors underlying schizophrenia are heterogeneous. 相似文献
20.
5至8岁儿童心理理论各成分的发展及其关系 总被引:3,自引:1,他引:3
使用故事-图片法,施测一级错误信念、二级错误信念、解释性心理理论和失言理解4类任务,考察5~8岁儿童多个层次的心理理论能力。结果表明,5岁儿童已经很好地理解一级错误信念。解释性心理理论和二级错误信念理解在类似的年龄发展起来,6~8岁是他们发展的关键时期。8岁儿童还不能很好的理解失言中所包含的认知和情感成分。相关和回归分析的结果表明,一级错误信念理解可能是后来发展的解释性心理理论、二级错误信念理解和失言理解的基础。 相似文献