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At least 19 recordsLinked to original sources
PubMed1992

The familial hypercholesterolemia (FH)-North Karelia mutation of the low density lipoprotein receptor gene deletes seven nucleotides of exon 6 and is a common cause of FH in Finland.

A mutation of the LDL receptor gene very common among Finnish patients with heterozygous familial hypercholesterolemia (FH) was identified. This mutation, designated as FH-North Karelia, deletes seven nucleotides from exon 6 of the LDL receptor gene, causes a translational frameshift, and is predicted to result in a truncated receptor protein. Only minute quantities of mRNA corresponding to the deleted gene were detected. Functional studies using cultured fibroblasts from the patients revealed that the FH-North Karelia gene is associated with a receptor-negative (or binding-defective) phenotype of FH. Carriers of the FH-North Karelia gene showed a typical xanthomatous form of FH, with mean serum total and LDL cholesterol levels of 12 and 10 mmol/liter, respectively. This mutation was found in 69 (34%) out of 201 nonrelated Finnish FH patients and was especially abundant (prevalence 79%) in patients from the eastern Finland. These results, combined with our earlier data on another LDL receptor gene deletion (FH-Helsinki), demonstrate that two "Finnish-type" mutant LDL receptor genes make up about two thirds of FH mutations in this country, reflecting a founder gene effect. This background provides good possibilities to examine whether genetic heterogeneity affects the clinical presentation or responsiveness to therapeutic interventions in FH.

Alleles↗
PubMed1990

Novel gene mutations at the low density lipoprotein receptor locus: FH-Kanazawa and FH-Okayama.

Gene mutations at the low density lipoprotein (LDL) receptor locus were screened in 210 alleles of Japanese patients with familial hypercholesterolaemia (FH). In the present study, two types of novel mutation were identified by genomic Southern blotting using human LDL receptor cDNA probes. An approximately 12 kb deletion including exons 2 and 3 (and possibly 4) was identified in a patient (M.I.). The patient with this mutant gene will be referred to as 'FH-Kanazawa'. Two patients born in Okayama Prefecture in Japan had another unique 13 kb partial deletion, from exons 7 to 14, in their LDL receptor genes (FH-Okayama). This mutant allele is the first reported case in which the central portion of the LDL receptor gene, the epidermal growth factor (EGF) precursor homology region, is eliminated.

Alleles↗
PubMedDate not supplied

Serum low density lipoprotein cholesterol level and cholesterol absorption efficiency are influenced by apolipoprotein B and E polymorphism and by the FH-Helsinki mutation of the low density lipoprotein receptor gene in familial hypercholesterolemia.

The aim of the present study was to evaluate the effect of variation of different gene loci separately and in concert on lipid metabolism in heterozygous familial hypercholesterolemia (FH). We assayed a unique low density lipoprotein (LDL) receptor gene defect (designated as FH-Helsinki), the XbaI polymorphism of the apolipoprotein (apo) B, phenotypes of the apo E, and determined the levels of serum lipoproteins, the efficiency of cholesterol absorption, and the values for several parameters of cholesterol metabolism in 51 unrelated patients with heterozygous FH. The genetic parameters were distributed independently of each other. Gender distribution and the prevalence of coronary artery disease were similar in the different apo E phenotypes, in the apo B genotypes, and in patients with and without the FH-Helsinki mutation. However, the FH-Helsinki mutation was associated with an increased body mass index. Serum LDL cholesterol was significantly elevated in patients with the FH-Helsinki mutation and the apo B X2 allele. Apo E phenotypes were not related to serum lipids per se, but the highest serum LDL cholesterol levels were measured in patients with the FH-Helsinki gene, apo E4 phenotype, and at least one X2 allele. Patients with the FH-Helsinki mutation and apo E4 phenotype had the highest cholesterol absorption efficiency. Cholesterol absorption was not related to serum lipids or lipoproteins, but LDL cholesterol was most elevated in patients with the most efficient cholesterol absorption. We conclude that in FH, diverse genetic factors exert individual and additive influences on serum LDL cholesterol levels.

Adolescent↗
PubMed1977

Intermodulation product pair 2f1 +/- fh: masking and growth.

To examine the question of whether the distortion product 2f1 - fh is unique--whether a special nonlinear mechanism is responsible for its production--estimates of 2f1 - fh and of 2f1 + fh amplitudes were obtained in three listeners. Threshold shifts measured with a tone-on-tone masking paradigm for each distortion product suggest that each have similar properties and are masked by other tones as if they had a physical realization in the cochlea. Their masking is not a function of stimulus fine-time structure. The 1 dB/dB growth of 2f1 - fh was not changed by rendering it inaudible as previously suggested. Possible explanations of the 1 dB/dB growth of 2f1 - fh compared with the accelerated growth of 2f1 + fh are examined.

Auditory Perception↗
PubMed2024

Case report: response to immunotherapy and association with the fh gene in hereditary leiomyomatosis and renal cell cancer-associated renal cell cancer.

Hereditary leiomyomatosis and renal cell cancer (HLRCC) is a rare autosomal dominant syndrome caused by a germline mutation in the fumarate hydratase (FH) gene that manifests with cutaneous leiomyomas, uterine fibroids, and renal cell cancer (RCC). Patients with HLRCC-associated RCC (HLRCC-RCC) have aggressive clinical courses, but there is no standardized therapy for advanced HLRCC-RCC. In this study, we described a case of aggressive HLRCC in a 33-year-old female who exhibited a novel heterozygous germline insertion mutation in exon 8 of the FH gene (c.1126 C > T; p.Q376*). The patient underwent laparoscopic resection of the right kidney, but metastases appeared within 3 months after surgery. Histological staining of the resected tumor revealed high expression levels of programmed cell death-ligand 1 (PD-L1). Therefore, the patient was treated with immunotherapy. The patient achieved a partial response to immunotherapy, and the treatment of metastatic lesions has continued to improve. A thorough literature review pinpointed 76 historical cases of HLRCC-RCC that had undergone immunotherapy. From this pool, 46 patients were selected for this study to scrutinize the association between mutations in the FH gene and the effectiveness of immunotherapy. Our results indicate that immunotherapy could significantly improve the overall survival (OS) of patients with HLRCC-RCC. However, no influence of different mutations in the FH germline gene on the therapeutic efficacy of immunotherapy was observed. Therefore, our study suggested that immunotherapy was an effective therapeutic option for patients with HLRCC regardless of the type of FH germline mutation.

Humans↗
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↗
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↗
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↗
PubMed1989

Finnish type of low density lipoprotein receptor gene mutation (FH-Helsinki) deletes exons encoding the carboxy-terminal part of the receptor and creates an internalization-defective phenotype.

A specific type of gene mutation affecting the LDL receptor has been found in many Finnish patients with familial hypercholesterolemia (FH). The mutant allele is characterized by a 9.5-kb deletion extending from intron 15 to exon 18. Molecular cloning and sequencing of a cDNA segment corresponding to the deleted allele indicated that the mutant receptor differs radically from the normal one because of loss of the domains encoded by exons 16, 17, and 18. The carboxy-terminal portion of the normal receptor, comprising the amino acids 750-839, has been replaced by an unrelated stretch of 55 amino acids. The mutant allele was found to occur in 23 (50%) of 46 unrelated FH patients with an established functional defect in the LDL receptor. In cultured fibroblasts from the FH patients with the 9.5-kb deletion, both receptor-mediated binding and internalization of 125I-LDL were lower than normal, the former, on average, by 25%, and the latter, on average, by 50%. This combined functional defect probably results from both impaired attachment and impaired internalization of the mutated receptor. It remains to be investigated whether this Finnish type of LDL receptor gene mutation, here designated FH-Helsinki, occurs in other ethnic groups.

Adult↗
PubMed1992

RFLPs of the LDL-receptor gene: their use in the diagnosis of FH and in evaluation of different levels of gene expression on normal subjects.

The usefulness of the RFLPs of the LDL-receptor gene in early diagnosis of Familial Hypercholesterolemia (FH) was investigated in 122 FH-families. Four RFLPs, produced by digestion with the enzymes PvuII, ApaLI and AvaII/XbaI were able to detect the affected gene and to follow the inheritance of the disease in 72 out of 97 families (74%). In the remaining 25 families, unambiguous diagnosis was possible in 66% of the cases by use of PvuII, ApaLI and BstEII/EcoRI RFLPs. The RFLPs were also useful to distinguish true homozygotes from compound heterozygotes and to detect families where recombination events occurred or where hypercholesterolemia was not due to a defect of the LDL-receptor gene. In a normal population PvuII RFLP account for 9.6% of the total variance of the LDL cholesterol levels adjusted for confounding variables. The P2 allele was associated with lower LDL cholesterol concentrations (average excess -9.1 mg/dl). This finding allows us to presume there is a DNA sequence, close to the variable PvuII cutting site in intron 15, which could act as an enhancer of the LDL-receptor gene expression.

Adult↗
PubMed1985

Linkage of loci encoding a kidney endothelial antigen and fumarate hydratase (Fh-1) in the rat.

In the rat a single locus, provisionally designated Eag-1, controls the expression of an antigen present on the endothelium of kidney peritubular capillaries and veins. We have examined the linkage relationship between Eag-1 and 10 polymorphic loci including hemoglobin b, fumarate hydratase, peptidase-3, urinary pepsinogen, seminal vesicle protein, glycerophosphate dehydrogenase, esterase-1, esterase-6, pinkeye, and hooded. Tissue samples from animals derived from (AUG X BN.1C)F1 X AUG and (AUG X BN.1C)F1 X BN.1C backcrosses were examined and a linkage association between Eag-1 and Fh-1 (EC 4.2.2.1) was detected. The linkage distance between Eag-1 and Fh-1 is 21 cM (chi 2 = 27.9; p = 0.00001) and this association defines the third locus in the tenth (X) linkage group of the rat.

Animals↗
PubMed1979

Further characterization of the human fumarase variant, FH 2--1.

1. Further investigation of fumarase using lymphoblastoid cells derived from an individual of the FH 2--1 phenotype has confirmed that the mitochondrial (FHM) and soluble (FHS) forms of fumarase are determined at the same structural locus. 2. The FH 2--1 variant is associated with enzyme deficiency: c. 70% of normal in lymphoblastoid cells and c. 20% of normal in red cells. 3. The pH optimum and apparent Michaelis constant of the variant fumarase were normal but heat-inactivation studies suggest that the isozymes containing polypeptides determined by the variant allele are unstable.

Cell Line↗
PubMed1992

A large deletion in the LDL receptor gene--the cause of familial hypercholesterolemia in three Italian families: a study that dates back to the 17th century (FH-Pavia).

In the LDL-receptor gene, a large rearrangement causing hypercholesterolemia was detected in three apparently unrelated families living in northern Italy. In all probands, binding, internalization, and degradation of 125I-LDL measured in skin fibroblasts were found to be 40%-50% of control values, indicative of heterozygous familial hypercholesterolemia (FH). Southern blot analysis revealed that the probands were heterozygous for a large (25-kb) deletion of the LDL-receptor gene eliminating exons 2-12. The affected subjects possessed two LDL-receptor mRNA species: one of normal size (5.3 kb) and one of smaller size (3.5 kb). In the latter mRNA, the coding sequence of exon 1 is joined to the coding sequence of exon 13, causing a change in the reading frame and thereby giving rise to a premature stop codon. The receptor protein deduced from the sequence of the defective mRNA is a short polypeptide of 29 amino acids, devoid of any function. Tracing these three families back to the 17th century, we found both their common ancestor and the possible origin of the mutation, in a region which is called "Lomellina" and which is located in southwest Lombardy, near the old city of Pavia. Therefore we named the mutation "FH-Pavia."

Adolescent↗
PubMedDate not supplied

[Depth of the curve of Spee in relation to FMA, FH, ANB and dental class].

The Authors have statistically evaluated (by student's t test) a series of 151 patients to evaluate the relation between the depth of Spee's curve and some skeletal cephalometric (FMA, FH and ANB) and occlusal (dental Class) parameters. The test has showed that there are not significant variations of Spee's curve depth in relation with vertical skeletal parameters (FMA and FH); on the contrary, it has showed significant variations as regards horizontal (ANB) and occlusal (dental Class) parameters. Particularly, the average value of Spee's curve of skeletal and dental III Classes has turned out to be systematically lower than that of other Classes.

Adolescent↗
PubMed1989

[Reverse occlusion diagnosed following angle SN to FH correction].

A 12-year-old boy was first seen with the chief complaint of reverse occlusion. His records allowed a class III malocclusion, crown fracture of 1 angle and -1.1 degrees angle SN to FH. Therefore, we corrected angle SN to FH from -1.1 degrees to 7 degrees and treated him with intermaxillary anchorage appliance and by the edgewise method.

Child↗
PubMed1989

[Properties of dental cyanoacrylate cement "FH" in the early period of setting].

The properties of dental cyanoacrylate cement "FH", which has protective and bacteriostatic effect on dental pulp, were compared with that of glass-ionomer cement. The operational properties such as setting time and consistency were good, but the mechanical properties as dental cement were a little inferior. These properties were affected definitely by temperature and humidity than the glass-ionomer cement, especially the influence of humidity was very high. However, the influence on bond strength was almost nothing, especially in the early period of setting. The factors affecting it could be very low disintegration. The bond strength for dentin after 24 hours the start of mixing of FH cement was much higher than that for enamel, but the strength rapidly decreased by thermal cycling between 4 degrees C and 50 degrees C in water.

Cyanoacrylates↗