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PubMed1977

Gene dosage effect for fumarate hydratase (FH; E.C. 4.2.1.2) in partial trisomy 1.

A strain of fibroblasts partially trisomic for the larger part of 1q (Norwood and Hoehn, 1974) contains about 1.5 times as much fumarate hydratase (FH) as various control-strains. This gene dosage effect was ascertained by (1) comparative measurements of the specific activity; (2) relating the specific activity of FH to that of reference enzymes, not influenced by the chromosomal anomaly; and (3) by immunoprecipitation methods, using a rabbit antiserum against pig heart FH which cross-reacts with the human enzyme. Among others, this gene dosage effect can be demonstrated numerically by the following parameters: Ratio of the average specific activity of FH in the trisomic strain to that of the control strains: 1.53. Corresponding ratio after dividing FH activity by that of reference enzymes; for acid phosphatase: 1.58, for glutamate dehydrogenase: 1.53. Average ratio of the immunoprecipitation areas obtained upon radial immunodiffusion according to Mancini et al. (1965): 1.56.

Acid Phosphatase↗
PubMed1998

Analysis of low density lipoprotein receptor gene mutations and microsatellite haplotypes in Greek FH heterozygous children: six independent ancestors account for 60% of probands.

This study reports the characterization of 60% of low density lipoprotein receptor (LDLR) gene mutations in 150 unrelated Greek familial hypercholesterolaemia (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 chromosome 19 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 (exon 6 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.

Adolescent↗
PubMed1993

Discrimination of (+)-3-PPP sites from DTG sites by FH-510, a novel potent sigma ligand, in rat brain.

The effect of 5,8-dimethyl-4-(2-di-n-propylaminoethyl)carbazol monohydrochloride (FH-510) on the binding of sigma ligands such as [3H](+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine ([3H](+)-3-PPP) and [3H]1,3-di-o-tolylguanidine ([3H]DTG) to rat brain membranes was studied. The inhibitory effect of FH-510 on [3H](+)-3-PPP binding to membranes of rat brain was 260 times more potent than that on [3H]DTG binding. Scatchard plot analysis showed that FH-510 inhibited [3H](+)-3-PPP binding in a competitive manner, while the inhibitory effect of FH-510 on [3H]DTG binding was noncompetitive. These results suggest that (+)-3-PPP sites could be discriminated from DTG sites, and that FH-510 binds preferentially to (+)-3-PPP recognition sites in rat brain.

Animals↗
PubMed2006

Effect of ezetimibe coadministered with statins in genotype-confirmed heterozygous FH patients.

We investigated the effect of statins and statins plus ezetimibe in 65 FH heterozygotes carrying LDLR-defective or LDLR-negative mutations as well as the effect of ezetimibe monotherapy in 50 hypercholesterolemic (HCH) patients intolerant to statins. PCSK9 and NPC1L1 genes were analysed to assess the role of genetic variants in response to therapy. In FH patients combined therapy reduced LDL-C by 57%, irrespective of the type of LDLR mutation. The additional decrease of plasma LDL-C induced by ezetimibe showed wide inter-individual variability (from -39% to -4.7%) and was negatively correlated with percent LDL-C decrease due to statin alone (r=-0.713, P<0.001). The variable response to statins was not due to PCSK9 gene variants associated with statin hyper-sensitivity. The highest response to ezetimibe was observed in a carrier of R174H substitution in NPC1L1, which had been found to be associated with high cholesterol absorption. In HCH patients, ezetimibe monotherapy induced a variable decrease of plasma LDL-C (from -47.7% to -13.4%). To investigate this variability, we sequenced NPC1L1 gene in patients with the highest and the lowest response to ezetimibe. This analysis showed a higher prevalence of the G allele of the c.816 C>G polymorphism (L272L) in hyper-responders, an observation confirmed also in FH patients hyper-responders to ezetimibe. In both FH and HCH patients, the G allele carriers tended to have a higher LDL-C reduction in response to ezetimibe. These observations suggest that in FH heterozygotes LDL-C reduction following combined therapy reflects a complex interplay between hepatic synthesis and intestinal absorption of cholesterol.

Adult↗
PubMed2006

Detection of a known mutation M412T in the LDL receptor in a Chinese Thai FH family.

BACKGROUND: Familial hypercholesterolemia (FH) is an autosomal dominant hypercholesterolemia caused by mutation in the LDL receptor gene. M412T mutation of the LDL receptor gene was previously observed in a single female patient diagnosed as having primary hypercholesterolemia. However, the analysis was incomplete and there was no confirmation of the M412T as the FH-causing mutation. We identified a mutation in the LDL receptor gene that underlines the severe FH phenotype in a new case, a female Chinese Thai patient. METHODS: Identification was made by PCR-SSCP, direct DNA sequencing and confirmed by allele specific amplification (ASA) originally designed for this current study. RESULTS: The entire LDL receptor gene screening revealed the genetic alteration that also caused M412T mutation in this new index patient. ASA analysis confirmed the DNA sequence in this patient and further identified three family members as M412T carriers. CONCLUSIONS: The finding of this mutation in 2 apparently unrelated index patients and the co-segregation of M412T and FH phenotype in the family of the present index case should provide evidence and confirm that the M412T was likely to be a disease-causing mutation. Whether M412T is common either as a founder or recurrent mutation among FH Chinese Thai population is unknown at present and remains to be clarified.

Adult↗
PubMedDate not supplied

Complement factor H: sequence analysis of 221 kb of human genomic DNA containing the entire fH, fHR-1 and fHR-3 genes.

Complement factor H (fH) is a member of a family of proteins involved in the regulation of complement activation (RCA). These proteins share a common structural motif, the Short Consensus Repeat (SCR), which is structurally conserved among related genes and between phylogenetically divergent species. fH is composed of 20 such SCRs and a variety of biological functions have been localised to specific SCR domains. The majority of individual SCRs identified are encoded by single exons, and processes such as gene conversion, duplication and exon shuffling have been implicated in the evolution and genomic radiation of SCR-encoding genes. We have analysed two GenBank sequence entries relating to two overlapping PAC clones sequenced at the Sanger Centre which contain the entire human fH gene and two adjacent fH-related (fHR) genes, fHR-1 and fHR-3. Here, we report the detailed analysis of the assembled 221 kb of contiguous, ungapped genomic sequence from human chromosome 1q32, in part employing the RUMMAGE-DP automated annotation tool. Genomic duplications involving fH and fHR exons were identified and Alu/L1 repeat dating established that the duplications occurred after the separation of rodent and primate lineages. The analysis indicates that retrotransposition as well as single and multiple exon duplication events are likely to have been involved in SCR radiation and RCA gene evolution, facilitated by conservation of splice-phasing and the single-exon, single-SCR nature of the encoded domains.

5' Untranslated Regions↗
PubMed2001

A molecular genetic service for diagnosing individuals with familial hypercholesterolaemia (FH) in the United Kingdom.

A genetic diagnostic service for familial hypercholesterolaemia (FH) has been established over the last 4 years in the Clinical Molecular Genetics Laboratory at Great Ormond Street Hospital for Children NHS Trust (GOSH), London. In total there have been 368 referrals; 227 probands and 141 family members, which have come from a number of lipid clinics and from general practitioners. FH is caused by mutations in the low-density lipoprotein receptor gene (LDLR) and these are analysed by SSCP, DNA sequencing and direct assays. The clinically indistinguishable disorder, familial defective apolipoprotein B100 (FDB) is caused by one of three mutations in the apolipoprotein B100 gene (APOB) which are analysed by direct assays. Mutations predicted to be pathogenic were found in 76 probands, 67 in LDLR (23 previously undescribed) and nine in APOB. The mutation detection rate was 53% in paediatric probands, 32% in adults with a 'definite' FH diagnosis (tendon xanthoma positive) and 14% in adults with a 'possible' FH diagnosis (tendon xanthoma negative). The predicted loss of sensitivity that would result from reducing the number of exons tested has been assessed, and a molecular screening strategy suitable for UK patients is proposed. A similar strategy may be useful for other countries where genetic heterogeneity results in a wide mutation spectrum for FH.

Adult↗
PubMed2003

Germline mutations in fumarate hydratase (FH) do not predispose to prostate cancer.

Inherited susceptibility to prostate cancer has been linked to a number of chromosomal regions, however no genes have been unequivocally shown to underlie reported linkages. The putative gene localised to chromosome 1q42-q43, has been designated PCaP. We have recently shown that germline mutations in the fumarate hydratase (FH) gene located on 1q43 cause smooth muscle tumours and renal cell carcinoma. It is conceivable that germline FH mutations might confer an increased risk of prostate cancer and underlie linkage of prostate cancer to PCaP. To examine this proposition we have analysed the entire coding region of FH in 160 prostate cancer cases in 77 multiple case families. No pathogenic mutations in FH were identified in any of the cases. This data makes it highly unlikely that mutations in FH confer susceptibility to prostate cancer.

Aged↗
PubMed1980

LDL receptor studies in children with heterozygous familial hypercholesterolemia (FH): measurement of sterol synthesis in blood lymphocytes.

Sterol synthesis was measured in lymphocytes from 48 members of 10 families with familial hypercholesterolemia (FH) under three sets of conditions. First the synthesis of LDL receptors and sterols were maximally stimulated by incubation of lymphocytes in lipoprotein-deficient serum. Secondly sterol synthesis was suppressed by the addition of LDL and thirdly sterol synthesis was maximally suppressed by the addition of 7-ketocholesterol. In five of the ten families LDL suppression of sterol synthesis in FH heterozygotes was only about half of the LDL suppression in normals. In four families, however, there was a considerable overlapping of LDL suppression in FH heterozygotes and normals. Finally in one family LDL suppression was strictly normal in FH heterozygotes who thus appear to have a different type of FH not involving an impaired LDL receptor function.

Adolescent↗
PubMedDate not supplied

New variant of low density lipoprotein receptor gene. FH-Tonami.

A new variant of the low density lipoprotein receptor (LDLR) gene was ascertained through Southern blotting analysis of LDLR genes of 35 unrelated Japanese patients with heterozygous familial hypercholesterolemia (FH). This mutant gene had a 6 kilobase deletion which had eliminated only exon 15, an exon that encodes the O-linked sugar domain. The mutation was recognized in two patients with heterozygous FH. We refer to these patients as 'FH-Tonami', since they were both born in the Japanese district of Tonami. Although there is no evidence of a relation between families, the possibility of a common ancestor with FH does exist. Neonatal diagnosis of FH in two fetuses from one family was possible through analyses of their LDLR genes in cord blood samples at delivery.

Genes↗
PubMed2002

Uptake of FH by two types of scavenger-like receptors in rat liver parenchymal cells in primary culture.

Several anionic proteins that are known to be substrates of scavenger receptors documented in the literature were selected and tested for their effects on the uptake of fractionated heparin (FH), an anionic macromolecular drug. The tests were made in rat liver parenchymal cells to characterize scavenger-like receptors involved in FH uptake, probing into substrate recognition characteristics in comparison with those of scavenger receptors. Although the uptake of FH was completely inhibited by dextran sulfate, a typical substrate of scavenger receptors, suggesting that scavenger-like receptors that have affinity for some anionic macromolecules are responsible for the uptake, it was not inhibited by acetylated low density lipoprotein (Ac-LDL), another typical substrate. Thus, the scavenger-like receptors were suggested to be different from the major scavenger receptors of classes A and B that are known to be sensitive to Ac-LDL. The uptake of FH was only partially inhibited by maleylated bovine serum albumin (Mal-BSA), suggesting that the scavenger-like receptors can be classified into two types in terms of sensitivity to Mal-BSA. The Mal-BSA-sensitive receptor was also found to be sensitive to oxidized low density lipoprotein (Ox-LDL). Kinetic analysis revealed that the binding capacity (Bmax) of the Mal-BSA-insensitive receptor was significantly larger than that of the Mal-BSA-sensitive one, though their dissociation constants (Kd) and apparent internalization rate constants (kint,app) were comparable. Information obtained in this study should be helpful for understanding the disposition mechanism of FH and also of anionic macromolecules and for developing delivery strategies, although the physiological roles and molecular identity of each receptor need to be further clarified in the future.

Animals↗
PubMed2002

Few FH mutations in sporadic counterparts of tumor types observed in hereditary leiomyomatosis and renal cell cancer families.

Loss of function mutations in the fumarate hydratase (fumarase, FH) gene were recently identified as the cause for dominantly inherited uterine and cutaneous leiomyomas and renal cell cancer. To further evaluate the role of FH in tumorigenesis, we screened FH mutations from tumor types seen in hereditary leiomyomatosis and renal cell cancer mutation carriers-41 uterine and 10 cutaneous leiomyomas, 52 renal cell carcinomas, 53 sarcomas, 29 prostate carcinomas, and 15 lobular breast carcinomas. Few mutations were detected. Biallelic inactivation of FH was found in one uterine leiomyosarcoma, one cutaneous leiomyoma, and one soft tissue sarcoma. Whereas the two former lesions were shown to originate from a germ-line mutation, the soft tissue sarcoma is to our knowledge the first example of purely somatic inactivation of FH in tumors.

Base Sequence↗
PubMed2025

Quantifying evidence for phenotypic specificity (PP4) for syndromic phenotypes: Large-scale integration of rare germline FH variants from diagnostic laboratory testing for HLRCC and renal cancer.

PURPOSE: Hereditary leiomyomatosis and renal cell cancer (HLRCC) is a rare cancer susceptibility syndrome exclusively attributable to pathogenic variants in FH (HGNC:3700). This article quantitatively weights the phenotypic context (PP4/PS4) of such very rare variants in FH. METHODS: We collated clinical diagnostic testing data on germline FH variants from 387 individuals with HLRCC and 1780 individuals with renal cancer and compared the frequency of "very-rare" variants in each phenotypic cohort with 562,295 population controls. We generated pan-gene very rare variant likelihood ratios (PG-VRV-LRs), domain-specific likelihood ratios for missense variants (DS-VRMV-LR) using spatial clustering analysis, and log2.08 likelihood ratios (LLRs) as applicable within the updated American College of Medical Genetics and Genomics/Association for Molecular Pathology variant classification framework. RESULTS: For HLRCC, the PG-VRV-LR was estimated to be 2669.4 (95% CI 1843.4-3881.2, LLR 10.77) for truncating variants and 214.7 (95% CI 185.0-246.9, LLR 7.33) for missense variants. For renal cancer, the PG-VRV-LR was 95.5 (95% CI 48.9-183.0, LLR 6.23) for truncating variants and 5.8 (95% CI 3.5-9.3, LLR 2.39) for missense variants. Clustering analysis in HLRCC cases revealed 3 "hotspot" regions wherein the DS-VRMV-LR increased to 1226.9. CONCLUSION: These data provide quantitative measures for very rare missense and truncating variants in FH, which reflect the differing phenotypic specificity of HLRCC and renal cancer and may be applicable in clinical variant classification.

Humans↗
PubMed1994

FH-Sydney 1 and 2: two novel frameshift mutations in exon 10 of the low-density lipoprotein receptor gene detected by heteroduplex formation.

We report two novel frameshift mutations in exon 10 of the low-density lipoprotein receptor gene that lead to familial hypercholesterolemia in separate lineages. The lesions, FH-Sydney 1 and FH-Sydney 2, were detected by a modified heteroduplex analysis of exon-specific polymerase chain reaction (PCR) amplified DNA, and characterized at the molecular level by sequencing. Restriction enzyme digestion of PCR amplified DNA confirmed the presence of the mutant alleles in affected family members and their absence in nonaffected family members in both lineages. FH-Sydney 1 is a 4-bp duplication at position 1373, while FH-Sydney 2 is a 2-bp deletion at position 1478. The predicted result of both mutations is the premature truncation of the receptor at stop codons generated downstream of the mutations. Neither mutation was detected in a survey of 54 unrelated familial hypercholesterolemia patients.

Base Sequence↗
PubMed1993

FH-510, a potent and selective ligand for rat brain sigma recognition sites.

FH-510 (5,8-dimethyl-4-(2-di-n-propylaminoethyl)carbazol) is a potent ligand for sigma ligand binding sites in rat brain membranes and has an IC50 value of 4.8 +/- 1.0 nM, which is comparable to that of haloperidol (2.2 +/- 0.2 nM). The high selectivity of FH-510 for sigma binding sites was evaluated by its lack of significant affinity for other binding sites, including those for dopamine D2 and phencyclidine. When administered to mice orally, FH-510 suppressed (+)-N-allylnormetazocine ((+)-SKF10,047)-induced stereotyped behavior with an ED25 value of 0.54 mg/kg, which is 14-fold more potent than that for (+)-alpha-(4-fluorophenyl)-4-(5-fluoro-2-pyrimidinyl)-1-piperazine butanol ((+)-BMY14802) (7.6 mg/kg). These results suggest that FH-510 may be a potent and selective sigma ligand.

Animals↗
PubMed2001

Fh-Souassi: a founder frameshift mutation in exon 10 of the LDL-receptor gene, associated with a mild phenotype in Tunisian families.

Familial hypercholesterolemia (FH) has a higher prevalence in central Tunisia together with a milder clinical expression than in western countries. The molecular basis of FH in Tunisia remains unknown. Our aim was to identify FH-causing mutations in three unrelated families (21 subjects) from the area of Souassi (central Tunisia). In probands with a presentation of homozygous FH, the promoter and 18 exons of the low density lipoprotein (LDL)-receptor gene were sequenced in both orientations. A novel complex frameshift mutation was identified in exon 10, nucleotides 1477-1479 (TCT) at Serine 472 were replaced by an insertion of seven nucleotides (AGAGACA), producing a premature termination codon 43 amino acids downstream. Binding of 125I-labelled LDL at 4 degrees C to cultured fibroblasts from two probands showed <2% normal LDL-receptor activity. AvaII digestion of PCR amplified genomic DNA identified this unique mutation in all families; homozygotes n=11, heterozygotes n=10. All mutation carriers shared the same haplotype (7 RFLPs), suggesting that they had a common ancestor. Despite high plasma LDL levels (m=16.0+/-3.0 mmol/l) and extravascular cholesterol deposits, most homozygotes were diagnosed after puberty and had a delayed onset of cardiovascular complications. Moreover, most heterozygotes were free of clinical signs and had plasma LDL cholesterol in the normal range (4.7+/-1.3 mmol/l) without taking any lipid-lowering medication. This mild clinical phenotype which contrasted with the severity of the mutation, could not be explained by specific apolipoprotein E or lipoprotein lipase alleles.

Adolescent↗
PubMed2002

Baseline lipid values partly determine the response to high-dose simvastatin in patients with familial hypercholesterolemia. The examination of probands and relatives in Statin studies with familial hypercholesterolemia (ExPRESS FH).

Statins decrease low-density lipoprotein cholesterol (LDL-C), and additionally, reduce triglycerides (TG) and raise high-density lipoprotein cholesterol (HDL-C) levels. This study evaluated the frequency of abnormal TG and HDL-C levels in patients with classical familial hypercholesterolemia (FH) and assessed therapeutic response at different baseline levels of these lipoproteins after 1 year of statin therapy. A total of 508 FH patients were included and mean LDL-C levels (8.37+/-2.12 mmol l(-1)) were severely elevated. After a washout period of 6 weeks, all patients started monotherapy with 80 mg simvastatin. Remarkably, LDL-C reduction was dependent on baseline LDL-C levels ranging from 51.1 to 45.5% in the top versus the bottom third of the LDL-C distribution. Unexpected in FH, elevated baseline TG levels were seen in 30% and low HDL-C levels in 15% of all patients. Also, changes in these lipoproteins were dependent on baseline levels; TG reduction was 40.7 versus 22.2% in patients with elevated versus normal levels, while HDL-C increase was 29.1 versus 11.4% in patients with low versus normal HDL-C levels. In conclusion, FH patients with the worst lipoprotein profile showed the greatest benefit from high-dose simvastatin treatment, since changes in these parameters were partly determined by baseline lipid levels.

Adolescent↗
PubMed1994

Basal plasma concentration of tissue plasminogen activator (t-PA) and the adaption to strenuous exercise in familial hypercholesterolaemia (FH).

Epidemiological studies have provided evidence that attenuated fibrinolytic activity and increased antigen levels of plasminogen activator are risk factors for coronary heart disease (CHD). In a comparative study, tissue plasminogen activator (t-PA) antigen and activity concentrations were examined in plasma from familial hypercholesterolaemia (FH) patients without manifest CHD (n = 14) and in age- and sex-matched normolipaemic controls (NLC) at rest and after the same bicycle exercise. The FH patients had higher systolic and diastolic blood pressure than their controls. The plasma level of t-PA antigen was higher in FH patients than in NLC under basal conditions (7.3 +/- 3.1 ng/ml vs 4.8 +/- 2.2 ng/ml, P = 0.022), whereas no difference was found in t-PA activity. Bicycle exercise induced a marked increase in t-PA antigen (P < 0.001 for both groups) which did not differ between groups. A more prominent rise in t-PA activity was observed among the FH patients during the exercise (1.71 +/- 0.99 vs 0.85 +/- 0.89 IU/ml, P = 0.24). Neither the basal level of thrombin-antithrombin III complex (TAT) nor the significant increase (P < 0.001 for both groups) induced by exercise differed between groups. A high t-PA antigen level may precede clinical manifestations of cardiovascular disease in patients with familial hypercholesterolaemia.

Adaptation, Physiological↗