共查询到20条相似文献,搜索用时 15 毫秒
1.
Hopkins PN Wu LL Stephenson SH Xin Y Katsumata H Nobe Y Nakajima T Hirayama T Emi M Williams RR 《Journal of human genetics》1999,44(6):364-367
Heterozygous familial hypercholesterolemia (FH) is a serious disorder causing twice normal low-density lipoprotein (LDL)
cholesterol levels early in childhood and very early coronary disease in both men and women. Treatment with multiple medications
together with diet can normalize cholesterol levels in many persons with FH and prevent or delay the development of coronary
atherosclerosis. Previously published blood cholesterol criteria greatly under-diagnosed new cases of FH among members of
known families with FH and over-diagnosed FH among participants of general population screening. Thus, there is a need for
accurate and genetically validated criteria for the early diagnosis of heterozygous FH. In the course of investigations of
coronary artery disease in Utah, we identified a family whose proband showed elevated plasma levels of LDL cholesterol. To
carry out molecular genetic diagnosis of the disease, we screened DNA samples for mutations in all 18 exons and the exon-intron
boundaries of the LDL receptor gene (LDLR). Novel point mutations were identified in the proband: a C-to-T transversion at nucleotide position 631, causing substitution
of tyrosine for histidine at codon 190 in exon 4 of the LDLR gene. The mutant allele-specific amplification method was used to examine 12 members of the family recruited for the diagnosis.
This method helped to unequivocally diagnose 7 individuals as heterozygous for this particular LDLR mutation, while excluding the remaining 5 individuals from carrier status with FH.
Received: March 29, 1999 / Accepted: June 18, 1999 相似文献
2.
Tsunenori Hirayama E. Yamaki Akira Hata Masahiro Tsuji Kiyoshi Hashimoto Masao Yamamoto M. Emi 《Journal of human genetics》1998,43(4):250-254
In the course of investigations of familial coronary artery disease in Hokkaido, the northern island of Japan, we identified
five families in which multiple members showed elevated plasma levels of low-density lipoprotein (LDL) cholesterol. To determine
the genetic etiology of their lipoprotein abnormalities, we screened DNA samples from these families for mutations in all
18 exons and the exon-intron boundaries of the LDL receptor (LDLR) gene. Novel point mutations were identified in each family: (1) a C-to-A transversion at nucleotide 285, causing a nonsense
mutation at codon 74, in eight members of family A; (2) a G-to-A transition at nucleotide 1136, causing substitution of Tyr
for Cys at codon 358, in six members of family B; (3) a C-to-T transition at nucleotide 1822, causing substitution of Ser
for Pro at codon 587, in five members of family C; (4) a one-base insertion of G to a five-G stretch at nucleotides 1774–1778
(codons 571–572), causing a frameshift, in six members of family D; and (5) a one-base deletion of T at nucleotide 1963–1964
(codon 634), causing a frameshift, in three members of family E. Through the molecular genetic approach a total of 28 individuals
in these families were diagnosed unequivocally as heterozygous for the respective LDLR mutations. This method also helped
us to diagnose familial hypercholesterolemia, or to exclude from carrier status, 11 children with borderline high cholesterol
levels.
Received: May 20, 1998 / Accepted: June 30, 1998 相似文献
3.
A Chinese homozygote of familial hypercholesterolemia: identification of a novel C263R mutation in the LDL receptor gene 总被引:1,自引:0,他引:1
Familial hypercholesterolemia (FH) is an autosomal dominant disorder caused by mutations in the low-density lipoprotein receptor
(LDLR) gene; it is characterized by a high concentration of LDL, which frequently gives rise to tendon xanthomas and premature
coronary artery disease (CAD). Individuals with heterozygous FH in China often exhibit a milder phenotype than those in other
countries. The diagnosis of heterozygous FH relies on the clinical phenotype and this does not always permit unequivocal diagnosis
of the disease. In the course of investigation of FH in a Chinese population sample, we found a family whose proband showed
a markedly raised concentration of LDL cholesterol in plasma, and the presence of skin and tendon xanthomata. We used single-strand
conformation polymorphism (SSCP) analysis to screen all the 18 exons and the exon-intron boundaries of the LDLR gene. One novel homozygous mutation, replacing T by C at nucleotide 850 in exon 6 was identified. This change substituted
cysteine for arginine at codon 263 (C263R) of the LDLR. By means of mutant allele-specific amplification, we unequivocally
diagnosed six heterozygotes with this novel mutation in the proband's family.
Received: October 30, 2000 / Accepted: December 18, 2000 相似文献
4.
Identification of the valine 408 to methionine mutation in the LDL receptor in a Greek patient with homozygous familial hypercholesterolemia 总被引:1,自引:0,他引:1
H. Schuster C. Manke J. Fischer C. Keller G. Wolfram N. Zöllnery 《Clinical genetics》1995,48(2):90-92
We have identified the cytosine to thymine change in the codon for amino acid 408 which causes valine to be replaced by methionine in exon 9 of the LDL receptor gene in a 12-year-old Greek boy living in Germany, with homozygous familial hypercholesterolemia, by using polymerase chain reaction-amplified genomic DNA and subsequent restriction digestion. Homozygosity was confirmed by direct DNA sequencing. The mutation was present in both his parents, and his brother, grandmother, uncle and cousin. Six restriction fragment length polymorphisms of the LDL receptor gene were used to determine the haplotype of the defective allele. The haplotype was different from the one reported earlier in African Afrikaners and from Holland. We conclude that the mutation in the Greek boy probably occurred as an independent mutation. Because the parents are from different areas in Greece, this mutation may be common in Greeks. 相似文献
5.
Hattori H Hirayama T Nobe Y Nagano M Kujiraoka T Egashira T Ishii J Tsuji M Emi M 《Journal of human genetics》2002,47(2):80-87
In the course of investigations of familial coronary artery disease in Hokkaido, the northland of Japan, we identified 13
families affected by familial hypercholesterolemia. Among them, we identified eight novel mutations of the low-density lipoprotein
(LDL) receptor gene, four of which caused frameshifts: (1) a 7-bp deletion at nucleotide (nt) 578–584 (codon 172–174, exon 4);
(2) a 14-bp insertion at 682 nt (codon 207–208, exon 4); (3) a 49-bp deletion at nt 943–991 (codon 294–310, exon 7); and (4)
a one-base insertion of C to a stretch of C3 at nucleotides 1687–1689 or codon 542. The others included (5) a T-to-C transition at nt 1072 causing substitution of Cys
for Arg at codon 337 (C337R, exon 8); (6) a splice-site G-to-T substitution in intron 11; (7) a splice-site G-to-C substitution
in intron 11; and (8) a G-to-T transition at nt 1731 causing substitution of Trp for Cys at codon 556 (W556C, exon 12). To
disclose the functional consequences of novel mutations, we characterized each of these mutations by two assays in peripheral
lymphocytes, i.e., uptake of fluorescently labeled LDL by LDL receptors, and measurement of cell surface-bound LDL receptor
protein using specific monoclonal antibody against LDL receptor.
Received: September 27, 2001 / Accepted: November 12, 2001 相似文献
6.
L.A. Pires R. Hegg F.R. Freitas E.R. Tavares C.P. Almeida E.C. Baracat R.C. Maranh?o 《Brazilian journal of medical and biological research》2012,45(6):557-564
Low-density lipoprotein (LDL) receptors are overexpressed in most neoplastic cell lines and provide a mechanism for the internalization and concentration of drug-laden nanoemulsions that bind to these receptors. The aim of the present study was to determine whether the administration of standard chemotherapeutic schemes can alter the expression of LDL and LDL receptor-related protein 1 (LRP-1) receptors in breast carcinoma. Fragments of tumoral and normal breast tissue from 16 consecutive volunteer women with breast cancer in stage II or III were obtained from biopsies before the beginning of neoadjuvant chemotherapy and after chemotherapy, from fragments excised during mastectomy. Tissues were analyzed by immunohistochemistry for both receptors. Because complete response to treatment was achieved in 4 patients, only the tumors from 12 were analyzed. Before chemotherapy, there was overexpression of LDL receptor in the tumoral tissue compared to normal breast tissue in 8 of these patients. LRP-1 receptor overexpression was observed in tumors of 4 patients. After chemotherapy, expression of both receptors decreased in the tumors of 6 patients, increased in 4 and was unchanged in 2. Nonetheless, even when chemotherapy reduced receptors expression, the expression was still above normal. The fact that chemotherapy does not impair LDL receptors expression supports the use of drug carrier systems that target neoplastic cells by the LDL receptor endocytic pathway in patients on conventional chemotherapy. 相似文献
7.
用卵磷脂/丙酮沉淀法测定经部分纯化的人胚肝LDL受体活性,结果发现,随着胎龄增加,肝脏LDL受体活性明显增高。与此同时,血清总胆固醇(TC)和LDL-胆固醇(LDL-C)水平进行性下降。胎龄与血清TC和LDL-C的相关系数分别为-0.80和-0.77,有显著意义(P<0.001)。进而发现,在胚肝LDL受体活性与血清TC和LDL-C之间也存在着明显的负相关,相关系数分别为-0.96和-0.95(P<0.001)。这一结果提示,在胎儿发育过程中,肝脏LDL受体对血胆固醇水平调节起着关键的作用。 相似文献
8.
9.
Mihaylov VA Horvath AD Savov AS Kurshelova EF Paskaleva ID Goudev AR Stoilov IR Ganev VS 《Journal of human genetics》2004,49(4):173-176
Familial hypercholesterolemia (FH) is a common, autosomal dominant disorder of lipid metabolism, caused by defects in the receptor-mediated uptake of LDL (low-density lipoproteins) due to mutations in the LDL receptor gene (LDLR). Mutations underlying FH in Bulgaria are largely unknown. The aim of the present study was to provide information about the spectrum of point mutations in LDLR in a sample of 45 Bulgarian patients with severe hypercholesterolemia. Exons 3, 4, 6, 8, 9, and 14, previously shown to be mutational hot spots in LDLR, were screened using PCR-single-strand conformation polymorphism (SSCP). Samples with abnormal SSCP patterns were sequenced. Three different, hitherto undescribed point mutations (367T>A, 377T>A, 917C>A) and two previously described mutations (858C>A and 1301C>T) in eight unrelated patients were identified; four of the detected point mutations being missense mutations and one, a nonsense mutation. One of the newly described point mutations (917C>A) is a base substitution at a nucleotide position, at which two other different base substitutions have already been reported. Thus, all three possible base substitutions at this nucleotide position have been detected, making it a hot spot for point mutations causing FH. This is the first such mutational hot spot described in exon 6 of LDLR. 相似文献
10.
Hiroaki Hattori Makoto Nagano Fujihiko Iwata Yasuhiko Homma Tohru Egashira Tomoo Okada 《Human mutation》1999,14(1):87-87
We used the denaturing gradient gel electrophoresis (DGGE) method to investigate 120 Japanese patients with familial hypercholesterolemia (FH) for mutations in the promoter region and the 18 exons and their flanking intron sequence of the low density lipoprotein (LDL) receptor gene. Fourteen aberrant DGGE patterns were found, and the underlying mutations were characterized by DNA sequencing. Five novel missense mutations (C317S, F382L A410T, L547V, and E693K), two nonsense mutations (W512X and K790X), four frameshift mutation (355del7, 1246ins5, 1687ins1, and 2035ins1), one splicing mutation (1845+2 T→C), and two inframe mutations (661ins21 and 1115del9/ins6) were identified. Six of these mutations (L547V, E693K, W512X, 355del7, 1687ins1, and 20354ins1) have not been described before in FH. These newly identified mutations cosegregated in their family members with defective LDL receptor activity and hypercholesterolemia, and are thought to be causal for the FH phenotype. These results demonstrate that there is a broad spectrum of mutations in the LDL receptor gene in the Japanese population. Hum Mutat 14:87, 1999. © 1999 Wiley‐Liss, Inc. 相似文献
11.
To obtain insight into the possibility that genetic variation of the structure of the low density lipoprotein (LDL) receptor protein could result in subtle changes of serum cholesterol levels, we used single-strand conformation polymorphism (SSCP) to screen all 18 exons of the LDL receptor gene in a panel of subjects with moderate hypercholesterolemia. One novel mutation, replacing C to T at nucleotide 313 and predicted to cause a substitution of serine for proline at codon 84, was identified in a single proband. A convenient PCR assay based on the use of primer-introduced restriction fragment length polymorphism was set up for the detection of this mutation. However, the pathophysiologic significance of the Pro84 → Ser replacement remains to be clarified, as serum LDL cholesterol levels were not significantly higher in mutation carriers vs. non-carriers in the affected family, and no other proband was identified, on screening of DNA samples from 350 Finns. The Pro84 → Ser mutation represents the second single-amino acid change of the LDL receptor protein so far reported which is not associated with the clinical phenotype of familial hypercholesterolemia. 相似文献
12.
Andrea Sánchez Paulina Bustos Paula Honorato Carlos F. Burgos Natalia Barriga Cinthia E. Jannes Katia Sáez Rodrigo Alonso Sylvia Asenjo Claudia Radojkovic 《Journal of clinical lipidology》2021,15(2):366-374.e1
BackgroundFamilial hypercholesterolemia (FH) is an inherited disorder mainly caused by mutations in the LDL receptor (LDL-R) and characterized by elevation of low-density lipoprotein cholesterol (LDL-C) levels and premature cardiovascular disease.ObjectiveIn this study, we evaluated the clinical phenotype of the p.Asp47Asn, described as an uncertain pathogenic variant, and its effect on the structure of LDL-R and ligand interactions with apolipoproteins.Methods27 children and adolescents with suspected FH diagnosis were recruited from a pediatric endocrinology outpatient clinic. Blood samples were collected after 12 h fasting for lipid profile analysis. DNA sequencing was performed for six FH-related genes by Ion Torrent PGM platform and copy number variation by MLPA. For index cases, a familial cascade screening was done restricted to the same mutation found in the index case. In silico analysis were developed to evaluate the binding capacity of LDL-R to apolipoproteins B100 and E.ResultsLipid profile in children and adolescents demonstrated higher LDL-C levels in p.Asp47Asn carriers compared to the wild type genotype. In silico analysis predicted a reduction in the binding capacity of the ligand-binding modules LA1-2 of p.Asp47Asn LDL-R for ApoB100 and ApoE, which was not produced by local structural changes or folding defects but as a consequence of a decreased apparent affinity for both apolipoproteins.ConclusionThe clinical phenotype and the structural effects of p.Asp47Asn LDL-R mutation suggest that this variant associates to FH. 相似文献
13.
DNA deletions in the low density lipoprotein (LDL) receptor gene in Danish families with familial hypercholesterolemia 总被引:5,自引:0,他引:5
N. S. Rüdiger E. M. Heinsvig F. A. Hansen O. FÆrgeman L. Bolund N. Gregersen 《Clinical genetics》1991,39(6):451-462
DNA samples from 25 unrelated Danish patients with familial hypercholesterolemia (FH) were screened by Southern blot hybridization to detect gross alterations in the low density lipoprotein (LDL) receptor gene. Three FH-patients were found to have a deletion. Two of these delete part of the cysteine rich domain, which comprises the ligand binding region of the LDL-receptor. The third deletion encompasses coding regions for the cytoplasmic part of the receptor. As two of these deletions could be equivalent to previously described LDL-receptor gene alterations, these data seem to support a notion of recombination hot spots which involve Alu-sequences. 相似文献
14.
An individual with a healthy phenotype in spite of a pathogenic LDL receptor mutation (C240F). 总被引:2,自引:0,他引:2
Ulf Ekstrm Magnus Abrahamson Claes-Henrik Florn Henrik Tollig Gran Wettrell Gerd Nilsson Xi-Ming Sun Anne K Soutar Peter Nilsson-Ehle 《Clinical genetics》1999,55(5):332-339
Familial hypercholesterolemia (FH) is caused by a defect in the function of the low density lipoprotein (LDL) receptor and inherited in an autosomal, codominant way. In this study we present a 13-year-old girl, compound heterozygote for the LDL receptor mutations C240F and Y167X. Fibroblasts from the patient showed very low cholesterol esterification rate, LDL uptake, and degradation compared to normal fibroblasts (< 2%, 8%, and < 2%, respectively). The C240F mutant was expressed in LDL receptor deficient CHOMldlA7 cells. Analysis of cell extracts by immunoblotting demonstrated delayed processing of the mutated LDL receptor, which was accumulated as a precursor protein of normal size. A high molecular weight form of the receptor was also detectable in these cells, which probably reflects cross-linking through the unpaired cysteine residue in the binding domain. Cells expressing the C240F mutant protein were unable to mediate uptake and degradation of LDL. The two siblings of the index case also carried the C240F mutation, but surprisingly one of them (a 17-year-old brother) showed no signs of hypercholesterolemia. This observation is consistent with the view that there may be cholesterol lowering mechanisms that can be activated, perhaps by mutations in known or hitherto unknown genes. 相似文献
15.
David W. Bilheimer Cara East Scott M. Grundy James J. Nora John M. Opitz James F. Reynolds 《American journal of medical genetics. Part A》1985,22(3):593-598
We have studied a family carrying a variant of the class 2 mutation of familial hypercholesterolemia (FH) in which there is unusual longevity and in which obligate heterozygotes did not express constant or statistically significant hypercholesterolemia. The heterozygotes have the same kinetic defect in the processing of low density lipoprotein (LDL) receptors in their fibroblasts and the reduced fractional catabolic rate for apoLDL that is characteristic of other patients with heterozygous FH. However, their plasma lipid and lipoprotein levels are not as strikingly abnormal because they have normal or near normal rates of apoLDL synthesis. 相似文献
16.
H. K. Jensen L. G. Jensen F. Heath F. Melsen P. S. Hansen H. Meinertz L. Bolund N. Gregersen O. Færgeman 《Clinical genetics》1996,50(5):388-392
We describe the clinical, biochemical, and genetic features of a patient with true homozygous familial hypercholesterolemia due to the D558N low-density lipoprotein receptor gene mutation, previously designated FH Cincinnati-4. Functional flow-cytometric analysis of the LDL receptorR protein on upregulated EB V-transformed lymphocytes indicated reduction of the number of receptors on the cell surface by 87% and reduction of receptor activity by 89% compared to control cells. With drugs and a portacaval shunt operation, performed when the patient was 15 years old, serum cholesterol was reduced from about 28 to about 15 mmol/l. He died at the age of 32 of a myocardial infarction. The autopsy showed generalized atherosclerosis, especially in the coronary arteries, which were severely stenosed proximally. A rare finding was a large intracranial xanthoma that apparently had been asymptomatic. 相似文献
17.
Takada D Emi M Ezura Y Nobe Y Kawamura K Iino Y Katayama Y Xin Y Wu LL Larringa-Shum S Stephenson SH Hunt SC Hopkins PN 《Journal of human genetics》2002,47(12):0656-0664
18.
19.
N Loux B Saint-Jore G Collod F Dairou P Benlian J Truffert B Dastugue P Douste-Blazy J L de Gennes C Junien 《Human mutation》1992,1(4):325-332
To investigate the molecular basis of familial hypercholesterolemia (FH) in France, we applied the single strand conformation polymorphism (SSCP) method to the promoter region and the 18 exons of the low density lipoprotein receptor (LDLR) gene. Seven probands, 4 heterozygotes, 2 compound heterozygotes, and 1 homozygote, belonging to FH families were tested. In all cases, previous genetic analysis and/or LDL receptor fibroblast assay had shown that the disease was due to defects in the LDLR gene. Out of the nine mutations expected, one nonsense mutation in exon 2 and six missense mutations were identified in exons 3, 6, 8, 11, and 15. Two of the latter were found in exon 6. In each family, cosegregation of the base substitution and the disease was observed. Ninety-five control subjects were screened for the presence of the six missense mutations. None was detected, implying that the mutations identified are deleterious. Our results indicate that the SSCP analysis of amplified genomic DNA fragments can be successfully used to rapidly screen mutation containing exons in large genes. Furthermore, all these mutations are newly described and demonstrate heterogeneity of LDLR gene mutations responsible for FH in the French population, as in other reported Caucasian populations. 相似文献
20.
Vilmundur Gudnason Gunnar Sigurdsson Henrik Nissen Steve E. Humphries 《Human mutation》1997,10(1):36-44
Haplotype analysis in 18 apparently unrelated families with familial hypercholesterolaemia (FH) in Iceland has identified at least five different chromosomes cosegregating with hypercholesterolaemia. The most common haplotype was identified in 11 of the 18 families, indicating a founder mutation responsible for FH in the Icelandic population. By using single-strand conformation polymorphism (SSCP) and direct sequencing of amplified DNA, we identified a novel mutation (a T to a C) in the second nucleotide in the 5′ part of intron 4 in the LDL receptor gene. This mutation was present in ˜60% of the FH families (10/18), supporting the prediction of a common founder. These families could be traced to a common ancestor in half of the cases by going back no further than the eighteenth century. The mutation was predicted to affect correct splicing of exon 4, and analysis at the cellular level demonstrated an abnormal mRNA containing intron 4 sequence in lymphoblastoid cells from a patient carrying this mutation. Translation of the mRNA would lead to a premature stop codon and a truncated nonfunctional protein of 285 amino acids. The novel sequence change created a new restriction site for the restriction endonuclease NlaIII, and using this assay, 29 unrelated individuals with possible FH attending a lipid clinic for treatment were examined for this mutation. Two individuals in this group of patients were found to be carriers of this mutation, supporting the suggestion of a founder mutation. Using this assay for the detection of FH in the Icelandic population should identify > 60% of these individuals. Hum Mutat 10:36–44, 1997. © 1997 Wiley-Liss, Inc. 相似文献