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1.
Rett syndrome is an X-linked dominant neurodevelopmental disorder caused by mutations in the MECP2 gene. Mutations have been demonstrated in more than 80% of females with typical features of Rett syndrome. We identified mutations in the MECP2 gene and documented the clinical manifestations in 65 Rett syndrome patients to characterize the genotype-phenotype spectrum. Bidirectional sequencing of the entire MECP2 coding region was performed. We diagnosed 65 patients with MECP2 mutations. Of these, 15 mutations had been reported previously and 13 are novel. Two patients have multiple deletions within the MECP2 gene. Eight common mutations were found in 43 of 65 patients (66.15%). The majority of patients with identified mutations have the classic Rett phenotype, and several had atypical phenotypes. MECP2 analysis identified mutations in almost all cases of typical Rett syndrome, as well as in some with atypical phenotypes. Eleven (20.4%) of the 54 patients with defined mutations and in whom phenotypic data were obtained did not develop acquired microcephaly. Hence, microcephaly at birth or absence of acquired microcephaly does not obviate the need for MECP2 analysis. We have initiated cascade testing starting with PCR analysis for common mutations followed by sequencing, when necessary. Analysis of common mutations before sequencing the entire gene is anticipated to be the most efficacious strategy to identify Rett syndrome gene mutations. 相似文献
2.
Luigi Bisceglia Maria Julia Calonge Luca Dello Strologo Gianfranco Rizzoni Luisa de Sanctis Michele Gallucci Ercole Beccia Xavier Testar Antonio Zorzano Xavier Estivill Leopoldo Zelante Manuel Palacin P. Gasparini Virginia Nunes 《Human genetics》1996,98(4):447-451
A cystinuria disease gene (rBAT) has recently been identified, but evidence strongly suggests that only Type-I cystinuria
is due to mutations in this gene. Sixteen point mutations and a large deletion causing the disease have so far been described
in the rBAT gene sequence. To identify new mutated alleles, genomic DNA was analyzed, after the determination of the entire
genomic structure of the rBAT gene, by RNA-single strand conformation polymorphism analysis, an accurate and sensitive method
able to detect nucleotide changes. Four new point mutations, a large deletion, and a common intragenic polymorphism were detected.
These new mutations increase to 22 the number of mutated alleles so far characterized in rBAT. In addition, the frequency
of 21 mutations was assessed in a sample of accurately defined Type-I cystinuria choromosomes. They account for about 58%
of all Type-I chromosomes, mutation M467T being the most common (0.26).
Received: 15 March 1996 / Revised: 17 May 1996 相似文献
3.
Mutations in the rhodopsin gene are the most common cause of retinitis pigmentosa (RP) among human patients. The nature of
the rhodopsin mutations has critical implications for the design of strategies for gene therapy. Nearly all rhodopsin mutations
are dominant. Although dominance does not arise because of haploinsufficiency, it is unclear whether it is caused by gain-of-function
or dominant-negative mutations. Current strategies for gene therapy have been devised to deal with toxic, gain-of-function
mutations. However, analysis of results of transgenic and targeted expression of various rhodopsin genes in mice suggests
that dominance may arise as a result of dominant-negative mutations. This has important consequences for gene therapy. The
effects of dominant-negative mutations can be alleviated, in principle, by supplementation with additional wild-type rhodopsin.
If added wild-type rhodopsin could slow retinal degeneration in human patients, as it does in mice, it would represent a valuable
new strategy for gene therapy of RP caused by dominant rhodopsin mutations. 相似文献
4.
Tyrosinase gene mutations in oculocutaneous albinism 1 (OCA1): definition of the phenotype 总被引:6,自引:0,他引:6
King RA Pietsch J Fryer JP Savage S Brott MJ Russell-Eggitt I Summers CG Oetting WS 《Human genetics》2003,113(6):502-513
Oculocutaneous albinism (OCA) is a common human genetic condition resulting from mutations in at least twelve different genes. OCA1 results from mutations of the tyrosinase gene and presents with the life-long absence of melanin pigment after birth (OCA1A) or with the development of minimal-to-moderate amounts of cutaneous and ocular pigment (OCA1B). Other types of OCA have variable amounts of cutaneous and ocular pigment. We hypothesized that white hair at birth indicates OCA1 and tested this in a sample of 120 probands with OCA and white hair at birth. We found that 102 (85%) of the probands had OCA1 with one or two identifiable tyrosinase gene mutations, with 169 (83%) of the 204 OCA1 tyrosinase gene alleles having identifiable mutations and 35 (17%) having no identifiable change in the coding, splice junction, or proximal promoter regions of the gene. The inability to identify the mutation was more common with OCA1B (24/35, 69%) than with OCA1A (11/35, 31%) alleles. Seven probands with no tyrosinase gene mutations were found to have OCA2 with one or two P gene mutations, and in eleven, no mutations were detected in either gene. We conclude that (1) the presence of white hair at birth is a useful clinical tool suggesting OCA1 in a child or adult with OCA, although OCA2 may also have this presentation; (2) the molecular analysis of the tyrosinase and P genes are necessary for precise diagnosis; and (3) the presence of alleles without identifiable mutations of the tyrosinase gene, particularly in OCA1B, suggests that more complex mutation mechanisms of this gene are common in OCA.Electronic database Information: accession numbers and URLs for data presented in this article are as follows:Albinism Database, , for a list of published mutations of the tyrosinase geneOnline Mendelian Inheritance in Man (OMIM), , for OCA1 (MIM 203100), OCA2 (MIM 203200) 相似文献
5.
Joanne Traeger-Synodinos Nicholas Mavroidis E. Kanavakis Eurydiki Drogari Steve E. Humphries Ian N. M. Day Christos Kattamis Nicholas Matsaniotis 《Human genetics》1998,102(3):343-347
This study reports the characterization of 60% of low density lipoprotein receptor (LDLR) gene mutations in 150unrelated
Greek familial hypercholes-terolaemia (FH) heterozygous children by the analysis of six LDLR gene mutations. The linkage disequilibrium
of two polymorphic microsatellites (D19S394 and D19S221) flanking the LDLR gene on chromosome19 to the four most common mutations
strongly suggests that each mutation is identical-by-descent in the probands included in this study (this is also supported
by the geographical distribution of FH families with these mutations throughout Greece) and permits an estimation of the number
of generations from a common ancestor for each mutation. The characterization of 60% of LDLR mutations in a representative
sample of Greek FH heterozygotes provides a basis for the diagnosis of FH through DNA analysis in Greece, by using single-strand
conformation polymorphism analysis followed by allele-specific oligonucleotide hybridization (exon6 mutations) or restriction
endonuclease analysis (C152R, V408M). A rapid diagnostic assay positive for the mutation has been developed for the most common
mutation, G528D. The application of simple DNA diagnostic assays for LDLR mutation analysis are appropriate for the early
identification of FH heterozygotes in Greece and are useful for the primary prevention of coronary artery disease.
Received: 7 July 1997 / Accepted: 5 November 1997 相似文献
6.
Detection of the most common G6PD gene mutations in Chinese using amplification refractory mutation system. 总被引:8,自引:0,他引:8
Glucose-6-phosphate dehydrogenase (G6PD) is the most common human enzymopathy. To date more than 122 mutations in the G6PD gene have been discovered, among which 12 point mutations are found in the Chinese. The 2 most common mutations, G1388A and G1376T, account for more than 50% of mutations representing various regions and ethnic groups in China. Setting up a simple and accurate method for detecting these mutations is not only useful for studying the frequency of the G6PD genotypes, but also for finding new mutations. The purpose of this study was to find a simple, inexpensive and accurate method for detecting these common mutations. The amplification refractory mutation system (ARMS) method was used in this study. Samples from 28 G6PD-deficient males were investigated. The natural and mismatched amplification and restriction enzyme digestion method was used as a standard method to evaluate the nature of the point mutations. Sixteen cases were found carrying the G1388A mutation and 12 the G1376T mutation. Fourteen cases of G1388A and 10 cases of G1376T were confirmed by ARMS. Four cases were not in concordance with the results obtained by the mismatched amplification-restriction enzyme digestion. These 4 cases were then judged by direct PCR sequencing at exon 12. The DNA sequencing data supported the results obtained by ARMS. Thus we concluded that the ARMS is a rapid, simple, inexpensive and accurate method for detecting the most common G6PD gene mutations among the Chinese. 相似文献
7.
Alteration of the p53 tumor suppressor gene is the most common genetic abnormality in human cancer. In breast cancer, depending on the stage of disease and method of detection, mutation rates of 25-60% have been observed. Multiple mutations of p53 gene in the same tumor however, are rarely reported. In this study we explored the frequency of multiple mutations of p53 gene in mammary carcinoma in a cohort of south Florida patients. Three hundred eighty-four cases of primary breast cancer diagnosed between 1984 and 1986 at the University of Miami, Jackson Medical Center were subjects of this study. Sequence analysis of exons 5 through 8 of p53 was performed on cloned PCR-amplified DNA of formalin-fixed, paraffin-embedded tumors. Two hundred thirty-four of 384 breast cancers (61%) had p53 mutation. Of those, 36 tumors showed more than one mutation; 31 tumors had two mutations, three showed three, one tumor had five mutations, and one case carried six mutations. The majority of mutations were missense (43) followed by silent (35); and most occurred within a single exon. Our study suggests that multiple mutations of p53 suppressor gene in breast cancer are more common than currently believed. 相似文献
8.
Elucidation of the gene defect in Marfan syndrome. Success by two complementary research strategies.
Marfan syndrome, which is characterized by manifestations in the skeletal, ocular and cardiovascular systems, is one of the most common inherited connective-tissue disorders. The independently performed genetic assignment of the Marfan locus and classical biochemical and immunohistochemical analyses complemented each other in the search for the Marfan gene defect and in 1991 the fibrillin gene in chromosome 15 was identified as the Marfan gene. So far, three mutations leading to the Marfan phenotype have been reported in this gene coding for a microfibrillar protein. The available data suggests a wide spectrum of different mutations of fibrillin and although mutations of the fibrillin gene account for the majority of Marfan cases, evidence also exists for locus heterogeneity in a minority of Marfan cases. 相似文献
9.
Mucopolysaccharidosis IVA: four new exonic mutations in patients with N-acetylgalactosamine-6-sulfate sulfatase deficiency. 总被引:1,自引:0,他引:1
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S. Tomatsu S. Fukuda A. Yamagishi A. Cooper J. F. Wraith T. Hori Z. Kato N. Yamada K. Isogai K. Sukegawa N. Kondo Y. Suzuki N. Shimozawa T. Orii 《American journal of human genetics》1996,58(5):950-962
We report four new mutations in Japanese patients with mucopolysaccharidosis IVA (MPSIVA) who were heterozygous for a common double gene deletion. A nonsense mutation of CAG to TAG at codon 148 in exon 4 was identified, resulting in a change of Q to a stop codon and three missense mutations. V (GTC) to A (GCC) at codon 138 in exon 4, P (CCC) to S (TCC) at codon 151 in exon 5, and P (CCC) to L (CTC) at codon 151 in exon 5. Introduction of these mutations into the normal GALNS cDNA and transient expression in cultured fibroblasts resulted in a significant decrease in the enzyme activity. V138A and Q148X mutations result in changes of restriction site, which were analyzed by restriction-enzyme assay. P151S and P151L mutations that did not alter the restriction site were detected by direct sequencing or allele specific oligohybridization. Detection of the double gene deletion was initially done using Southern blots and was confirmed by PCR. Haplotypes were determined using seven polymorphisms to the GALNS locus in families with the double gene deletion. Haplotype analysis showed that the common double gene deletion occurred on a single haplotype, except for some variation in a VNTR-like polymorphism. This finding is consistent with a common founder for all individuals with this mutation. 相似文献
10.
11.
Serdar Oztuzcu Mustafa Ulaşlı Sercan Ergun Yusuf Ziya Iğci Mehri Iğci Recep Bayraktar Gülper Nacarkahya Ali Tamer Muammer Özgür Çevik Ecir Ali Çakmak Ahmet Arslan 《Molecular biology reports》2014,41(4):2601-2607
Familial mediterranean fever (FMF) is an autosomal recessive autoinflammatory disorder (MIM# 249100), particularly common in populations of Mediterranean extraction. MEFV gene, responsible for FMF, encoding pyrin has recently been mapped to chromosome 16p13.3. In the present study, 3,341 unrelated patients with the suspicion of FMF in south-east part of Turkey between the years 2009 and 2013 were enrolled and genomic sequences of exon 2 and exon 10 of the MEFV gene were scanned for mutations by direct sequencing. We identified 43 different type of mutations and 9 of them were novel. DNA was amplified by PCR and subjected to direct sequencing for the detection of MEFV gene mutations. Among the 3,341 patients, 1,598 (47.8 %) were males and 1,743 (52.1 %) were females. The mutations were heterozygous in 806 (62.3 %), compound heterozygous in 188 (14.5 %), homozygous in 281 (21.8 %) and mutations had complex genotype in 17 (1.32 %) patients. No mutation was detected in 2,051 (61.4 %) patients. The most frequent mutations were M694V, E148Q, M680I(G/C) and V726A. We could not find any significant differences between the two common mutations according to the gender. Molecular diagnosis of MEFV is a useful tool in clinical practice, thus a future study relating to genotype/phenotype correlation of FMF in more and larger group in Turkish population involving the whole MEFV gene mutations is necessary. 相似文献
12.
E. Serra E. Ars A. Ravella A. Sánchez S. Puig T. Rosenbaum X. Estivill C. Lázaro 《Human genetics》2001,108(5):416-429
Neurofibromas, benign tumors that originate from the peripheral nerve sheath, are a hallmark of neurofibromatosis type 1 (NF1). Although loss of heterozygosity (LOH) is a common phenomenon in this neoplasia, it only accounts for part of the somatic NF1 mutations found. Somatic point mutations or the presence of "two hits" in the NF1 gene have only been reported for a few neurofibromas. The large size of the NF1 gene together with the multicellular composition of these tumors has greatly hampered their molecular characterization. Here, we present the somatic NF1 mutational analysis of the whole set of neurofibromas studied by our group and consisting in 126 tumors derived from 32 NF1 patients. We report the identification of 45 independent somatic NF1 mutations, 20 of which are reported for the first time. Different types of point mutations together with LOH affecting the NF1 gene and its surrounding region or extending along the 17q arm have been found. Among point mutations, those affecting the correct splicing of the NF1 gene are common, coinciding with results reported on germline NF1 mutations. In most cases, we have been able to confirm that both copies of the NF1 gene are inactivated. We have also found that both somatic and germline mutations can be expressed at the RNA level in the neoplastic cells. Furthermore, we have observed that the study of more than one tumor derived from the same patient is useful for the identification of the germline mutation. Finally, we have noticed that the culture of neurofibromas and their fibroblast clearance facilitates LOH detection in cases in which it is difficult to determine. 相似文献
13.
In this study we have performed analyses of apolipoprotein (apo) B at both the protein and gene level to search for mutations
of the apoB gene causing hypocholesterolemia among 71 Norwegian subjects. None of the subjects possessed apoB of abnormal
molecular weight as determined by SDS-polyacrylamide gel electrophoresis of lipoproteins in the 1.025 g/ml–1.063 g/ml density
range. Screening for mutations in exon 26 of the apoB gene by analysis of single-strand conformation polymorphisms followed
by DNA sequencing, revealed seven point mutations of which one is a novel mutation. Five of the mutations were missense mutations
and two were sense mutations. A group of 143 hypercholesterolemic, nonfamilial hypercholesterolemia subjects served as a control
group for comparisons of gene frequencies. The only statistically significant finding was that mutation 8344T at codon 2712
was more common among those with hypocholesterolemia. This finding is in accord with previous reports.
Received: 20 January 1997 / Accepted: 25 September 1997 相似文献
14.
Genetic selection of intragenic suppressor mutations that reverse the effect of common p53 cancer mutations. 总被引:8,自引:1,他引:7
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Several lines of evidence suggest that the presence of the wild-type tumor suppressor gene p53 in human cancers correlates well with successful anti-cancer therapy. Restoration of wild-type p53 function to cancer cells that have lost it might therefore improve treatment outcomes. Using a systematic yeast genetic approach, we selected second-site suppressor mutations that can overcome the deleterious effects of common p53 cancer mutations in human cells. We identified several suppressor mutations for the V143A, G245S and R249S cancer mutations. The beneficial effects of these suppressor mutations were demonstrated using mammalian reporter gene and apoptosis assays. Further experiments showed that these suppressor mutations could override additional p53 cancer mutations. The mechanisms of such suppressor mutations can be elucidated by structural studies, ultimately leading to a framework for the discovery of small molecules able to stabilize p53 mutants. 相似文献
15.
Mediterranean fever gene mutations: correlation with cytotoxic T‐lymphocyte‐associated antigen 4 gene polymorphism
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16.
Cloning and characterization of the Escherichia coli lit gene, which blocks bacteriophage T4 late gene expression. 总被引:5,自引:2,他引:3
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Escherichia coli lit mutations inhibit gene expression late in infection by bacteriophage T4. We cloned the lit gene from wild-type E. coli and three independent lit mutants. We present evidence that lit mutations [renamed lit(Con) mutations] cause overproduction of the lit gene product and that overproduction of this product causes the inhibition of gene expression. We also present evidence that the lit gene product is nonessential for E. coli growth, although the gene is common to most E. coli K-12 strains. 相似文献
17.
眼皮肤白化病Ⅱ型相关的P基因突变与DNA多态性 总被引:3,自引:0,他引:3
眼皮肤白化病Ⅱ型(OCA2)是白化病中最常见的类型,呈常染色体隐性遗传。P基因为其致病基因,定位于15q11.1-q12,由24个外显子和23个内含子构成。P基因编码838个氨基酸残基构成的110 KDa跨膜蛋白,该蛋白含12个跨膜区,其确切功能尚未完全清楚。迄今至少已报道P基因内60种导致OCA2的病理性突变和43种多态性变异。病理突变主要为错义突变、无义突变、移码突变和剪切位点突变,多数位于肽链的C末端,但并不象OCA1的TYR基因突变那样多成簇出现。P基因多态性变异中的大部分位于外显子,这增加了对致病性突变定义的难度,其中一些导致氨基酸替换的多态性变异可能与正常人色素沉着的表型变 相似文献
18.
A substitution mutation in the myosin binding protein C gene in ragdoll hypertrophic cardiomyopathy 总被引:4,自引:0,他引:4
Familial hypertrophic cardiomyopathy (HCM) is a primary myocardial disease with a prevalence of 1 in 500 in human beings. Causative mutations have been identified in several sarcomeric genes, including the cardiac myosin binding protein C (MYBPC3) gene. Heritable HCM also exists in a large-animal model, the cat, and we have previously reported a mutation in the MYBPC3 gene in the Maine coon breed. We now report a separate mutation in the MYBPC3 gene in ragdoll cats with HCM. The mutation changes a conserved arginine to tryptophan and appears to alter the protein structure. The ragdoll is not related to the Maine coon and the mutation identified is in a domain different from that of the previously identified feline mutation. The identification of two separate mutations within this gene in unrelated breeds suggests that these mutations occurred independently rather than being passed on from a common founder. 相似文献
19.
McArdle disease, one of the most common metabolic causes of exercise intolerance and recurrent myoglobinuria, is due to biochemical defects of the muscle isoform of glycogen phosphorylase. The gene for myophosphorylase (PGYM) is on chromosome 11, and 33 distinct mutations have been identified in patients from all over the world. In Caucasians, a nonsense mutation in exon 1 (R49X) is common enough to warrant screening of genomic DNA from blood before considering muscle biopsy. Other mutations are prevalent in different ethnic groups or are "private". Mutations are spread throughout the gene and there is no clear genotype:phenotype correlation. High-protein diet and aerobic exercise are beneficial, and gene therapy appears promising. 相似文献
20.
This paper studies gene trees in subdivided populations which are constructed as perfect phylogenies from the pattern of mutations in a sample of DNA sequences and presents a new recursion for the probability distribution of such gene trees. The underlying evolutionary model is the coalescent process in a subdivided population. The infinitely-many-sites model of mutation is assumed. Ancestral inference questions that are discussed are maximum likelihood estimation of migration and mutation rates; detection of population growth by likelihood techniques; determining the distribution of the time to the most recent common ancestor of a sample of sequences; determining the distribution of the age of the mutations on the gene tree; determining in which subpopulation the most recent common ancestor of all the sequences was; determining subpopulation ancestors, where they were, and times to them; and determining in which subpopulations mutations occurred. A computational technique of Griffiths and Tavaré used is a computer intensive Markov chain simulation, which simulates gene trees conditional on their topology implied by the mutation pattern in the sample of DNA sequences. The software GENETREE, which implements these ancestral inference techniques, is available. 相似文献