Search PubMed⌕ Search

Biomedical subjects

R R Frants

Publications and source records attributed to R R Frants.

At least 145 records · Page 8Linked to original sources
PubMed1994

Facioscapulohumeral muscular dystrophy in early childhood.

OBJECTIVE: To determine the occurrence and the clinical and genetic variability of early-onset facioscapulohumeral muscular dystrophy (FSHD). DESIGN: Patients were derived from a large series of patients who participated in a genetic study of FSHD in the Netherlands. PATIENTS: A group of 96 patients of 17 families with autosomal dominant FSHD, nine sporadic cases of FSHD, and 35 children at risk for having the FSHD gene was searched for the presence of early-onset cases. Criteria for early-onset FSHD were (1) signs or symptoms of facial weakness before the age of 5 years and (2) signs or symptoms of shoulder girdle weakness before the age of 10 years. RESULTS: Six early-onset cases (four familial, two sporadic) were identified. Four of five cases showed an abnormal DNA fragment with the probe p13E-11, which has been shown to detect DNA rearrangements in FSHD patients. The clinical symptoms in these early-onset cases showed great variability with respect to rate of progression of muscle weakness, the association of hearing loss and retinopathy, and the expression of the disorder in parents and siblings. CONCLUSIONS: Infantile FSHD has been suggested to be a separate form of the disease, often accompanied by sensorineural hearing loss and retinal telangiectasia. Our findings, as well as the fact that both hearing loss and retinal vasculopathy have been recently shown to be part of FSHD, suggest that early-onset FSHD is not a separate entity, but part of a wide clinical spectrum of FSHD.

Adolescent↗
PubMed1994

Genetic heterogeneity of apolipoprotein E and its influence on plasma lipid and lipoprotein levels.

Apolipoprotein E (apoE) is one of the major protein constituents of chylomicron and very-low-density lipoprotein (VLDL) remnants and plays a central role as a ligand in the receptor-mediated uptake of these particles by the liver. Including the most common variant, apoE3, 30 apoE variants have been characterized. At present, 14 apoE variants have been found to be associated with familial dysbetalipoproteinemia, a genetic lipid disorder characterized by elevated plasma cholesterol and triglyceride levels and an increased risk for atherosclerosis. Seven apoE variants were found to be associated with other forms of hyperlipoproteinemia. This report presents an overview of all currently known apoE variants and their effects on lipoprotein metabolism.

Alleles↗
PubMed1994

Dominant congenital benign spinal muscular atrophy.

The affected members of the family described in this article exhibit congenital nonprogressive atrophy and weakness of lower limb muscles in association with contractures. Clinical and laboratory findings support a dominant lower motor neuron disorder. DNA analysis excluded linkage of the disease with SMA markers on the long arm of chromosome 5. The condition must be differentiated from congenital and infantile SMA, from "arthrogryposis multiplex congenita, distal type," and from non hereditary types of congenital arthrogryposis.

Adolescent↗
PubMed1994

Chromosome 4q35 haplotypes and DNA rearrangements segregating in affected subjects of 19 Italian families with facioscapulohumeral muscular dystrophy (FSHD).

Four DNA markers on the distal long arm of chromosome 4 have been analyzed for their linkage to facioscapulohumeral muscular dystrophy locus (FSHD) in a series of 16 Italian families. We found that, in two families, the disease is not linked to the 4q35 markers, indicating the presence of genetic heterogeneity among Italian FSHD families. Linkage analysis in the remaining families supports the order cen-D4S171-D4S163-D4S139-D4S810-FSHD-qter, in agreement with the physical map from the literature. EcoRI digestion and hybridization with the distal marker p13E-11 (D4S810)1 detected DNA rearrangements in the affected members of both sporadic and familial cases of FSHD, with family-specific fragments ranging in size between 15 kb and 28 kb. In three sporadic FSHD cases, the appearance of a new "small" fragment not present in either parent was clearly associated with the development of FSHD disease. However, in the familial cases analyzed, we observed two recombinations between all four 4q35 markers and the disease locus in apparently normal subjects, leaving open the possibility of nonpenetrance of the FSHD mutation.

Adolescent↗
PubMed1994

Pure hereditary spastic paraparesis: an exclusion map covering more than 40% of the autosomal genome.

Pure hereditary spastic paraparesis (HSP) is an upper motor neuron syndrome clinically characterized by slowly progressive weakness and spasticity of the legs. To determine the chromosomal location of the genetic defect, a five-generational Dutch family with autosomal dominant pure HSP was subjected to linkage studies. Analysis was carried out on 48 members spanning three generations, of whom 23 individuals are definitely affected. By screening the genome with a total of 167 microsatellite markers distributed over all autosomes, an exclusion map for HSP was constructed. Depending on the actual size of the human genome, our exclusion map covered between 40% and 65% of its autosomal length. Loci on chromosomes 1, 8, 13, 14, and 18 showed slightly positive lod scores. The areas around these loci were investigated more closely, but no conclusive evidence for, or against, linkage could be obtained.

Chromosome Mapping↗
PubMed1994

Diet-induced hypercholesterolemia and atherosclerosis in heterozygous apolipoprotein E-deficient mice.

Apolipoprotein (apo) E is a ligand for the receptor-mediated uptake of lipoprotein remnant particles. Complete absence of apo E in humans leads to a severe form of type III hyperlipoproteinemia. We have used targeted inactivation in murine embryonic stem cells, as also described by others, to specifically study the effects of heterozygous Apoe gene loss on the development of hyperlipidemia. After 6 weeks on a severe semi-synthetic atherogenic diet, heterozygous null mutants, with only one functional Apoe alle, developed hypercholesterolemia as compared with controls (10.1 mM vs. 4.7 mM serum cholesterol). Interestingly, serum cholesterol levels in female heterozygotes were doubled as compared with male heterozygotes (15.0 mM vs. 7.5 mM). On this diet, heterozygous apo E deficient mice also showed an increased susceptibility to atherosclerosis, depending on gender (mean lesion area per section of 9524 microns 2 vs. 61,388 microns 2 for males and females, respectively), whereas wild-type mice displayed far fewer lesions (354 microns 2 and 9196 microns 2 for males and females, respectively). This study indicates that a subnormal expression-level of the Apoe gene leads to hypercholesterolemia and, consequently, to an increased susceptibility to the development of atherosclerosis.

Aging↗
PubMed1994

Lipoprotein profiles in a family with two mutants of apolipoprotein E: possible association with hypertriglyceridaemia but not with dysbetalipoproteinaemia.

1. The plasma lipoprotein profiles of eight members of a Dutch pedigree spanning three generations where two rare apolipoprotein E mutants, APOE*3(Cys-112-->Arg; Arg-251-->Gly) and APOE*2(Val-236-->Glu), segregate were analysed to determine whether the APOE mutants were associated with dyslipidaemia. 2. The proband, a 51-year-old Caucasian male, was a carrier of APOE*3(Cys-112-->Arg; Arg-251-->Gly) and his spouse was a carrier of APOE*2(Val-236-->Glu). Four other family members were carriers of one or both of the mutant APOE genes. 3. The plasma cholesterol and triacylglycerol concentrations were markedly elevated in the proband and were classified as type IV hyperlipoproteinaemia. The plasma triacylglycerol concentration was moderately increased in a sister, who was a carrier of APOE*3(Cys-112-->Arg; Arg-251-->Gly), and in the son, who was a compound heterozygote for both mutant APOE alleles. Normal plasma lipid levels were observed in all other family members. In the plasma samples of the proband and his family members beta-very-low-density lipoprotein was not detectable and the molar ratio of very-low-density lipoprotein-cholesterol to very-low-density lipoprotein-triacylglycerol was less than 0.9. The concentration of intermediate-density lipoprotein was within normal limits. 4. None of the family members carrying APOE*3-(Cys-112-->Arg; Arg-251-->Gly) and/or APOE*2(Val-236-->Glu) exhibited lipoprotein abnormalities characteristic of familial dysbetalipoproteinaemia, although three family members carrying APOE*3-(Cys-112-->Arg; Arg-251-->Gly) showed hypertriglyceridaemia.

Apolipoproteins E↗
PubMed1994

Genetics of seven Dutch familial atypical multiple mole-melanoma syndrome families: a review of linkage results including chromosomes 1 and 9.

Familial atypical multiple mole-melanoma syndrome is characterized by the familial occurrence of malignant melanoma of the skin in combination with multiple atypical precursor nevi; its pattern shows a dominant inheritance in pedigrees. During the last 5 years we have performed linkage analysis in seven Dutch familial atypical multiple mole-melanoma families to define the locus of the underlying gene defect. In 1989 it was reported that in familial melanoma families in the USA a disease-gene was located on chromosome 1p. However, in the Dutch families we could exclude this chromosome from harboring the Dutch familial atypical multiple mole-melanoma gene. Very recently a new candidate locus was found on chromosome 9p, which could be confirmed in our family material. A melanoma-associated gene was linked to several markers on chromosome 9p21. In a linkage analysis in which only melanoma patients were considered as affected, marker D9S171 showed a maximum lod score of 3.11 (theta 0.0). After introducing family members with 10 or more, or five or more, atypical nevi as affected in addition to the melanoma patients, the maximum lod score rose to 4.88 (theta 0.05) and 3.79 (theta 0.07), respectively. Interestingly, the sharing of a unique chromosome 9p21 haplotype among most melanoma patients in the families from two different villages suggests that an old common mutation is present in the Leiden region.

Adolescent↗
PubMed1994

Effect of insulin resistance, apoE2 allele, and smoking on combined hyperlipidemia.

Combined hyperlipidemia may result from the interaction of several metabolic and environmental factors. We explored to what extent fasting insulin concentration, apolipoprotein (apo) E2 frequency, and cigarette smoking explained the serum levels of triglyceride and high-density lipoprotein cholesterol (HDL-C) in patients with combined hyperlipidemia. Forty-nine untreated patients with combined hyperlipidemia were compared with 49 hypercholesterolemic patients who were matched for gender, age, and body mass index. All laboratory values were obtained after 9 weeks of standardized dietary intake and after an overnight fast. The patients with combined hyperlipidemia had a significantly higher (33 pmol/L, 50%) mean insulin concentration than matched hypercholesterolemic control subjects, indicating that the combined hyperlipidemic patients were more insulin resistant. However, the differences in the fasting insulin and triglyceride concentrations within the pairs were only slightly correlated (adjusted r = .29). The combined hyperlipidemic patients were also characterized by a higher frequency of apoE2 alleles (25% versus 6%) and smokers (41% versus 16%). In a matched multiple linear regression model, the differences in insulin concentration, apoE2 allele frequency, and smoking explained 12%, 8%, and 9%, respectively, of the mean paired difference in triglyceride concentration. The differences in insulin concentration or apoE2 allele frequency did not significantly explain the mean paired difference in HDL-C concentration, whereas smoking explained 17% of the difference. In conclusion, fasting insulin concentration, the presence of the apoE2 allele, and smoking may explain 30% of the hypertriglyceridemia and the low levels of HDL-C in nonobese patients with combined hyperlipidemia.(ABSTRACT TRUNCATED AT 250 WORDS)

Alleles↗
PubMed1994

Plasma lipoproteins in familial dysbetalipoproteinemia associated with apolipoproteins E2(Arg158-->Cys), E3-Leiden, and E2(Lys146-->Gln), and effects of treatment with simvastatin.

Using a density-gradient ultracentrifugation technique, we analyzed in detail the plasma lipoprotein profiles of 18 patients with familial dysbetalipoproteinemia (FD) who had apolipoprotein (apo) E2(Arg158-->Cys) homozygosity (the E2-158 variant, n = 6), apoE3-Leiden heterozygosity (the E3-Leiden variant, n = 6), or apoE2(Lys146-->Gln) heterozygosity (the E2-146 variant, n = 6), with average plasma cholesterol concentrations of 8.99 +/- 1.34 mmol/L, 9.29 +/- 1.55 mmol/L, and 8.46 +/- 1.10 mmol/L, respectively. No significant differences in sex, age, body mass index, dietary habits, and standard laboratory tests between the three groups were observed. The lipoprotein profiles of all FD patients were characterized by higher concentrations of very-low-density lipoprotein (VLDL) 1, VLDL2, and intermediate-density lipoprotein (IDL) and a higher cholesteryl ester content of VLDL1 and VLDL2 than in 6 normolipidemic control subjects with an average plasma cholesterol concentration of 5.90 +/- 0.53 mmol/L. Major differences between the plasma lipoprotein profiles of patients with the E2-158 variant, the E3-Leiden variant, and the E2-146 variant and the normolipidemic control subjects were in IDL cholesterol concentration (1.70 +/- 0.26, 1.50 +/- 0.26, 1.05 +/- 0.36, and 0.47 +/- 0.14 mmol/L, respectively), LDL cholesterol concentration (1.83 +/- 0.50, 3.09 +/- 0.32, 3.79 +/- 0.76, and 3.77 +/- 0.56 mmol/L, respectively), and the molar ratio of IDL cholesterol to LDL cholesterol (0.98 +/- 0.28, 0.48 +/- 0.04, 0.28 +/- 0.09, and 0.12 +/- 0.03, respectively). After 10 weeks of simvastatin treatment the concentrations of plasma cholesterol, VLDL2 cholesterol, IDL cholesterol, and LDL cholesterol in 3 patients with the E2-158 variant fell significantly, by 46%, 56%, 53%, and 48%, respectively; they also fell in 3 patients with the E3-Leiden variant, by 48%, 54%, 57%, and 52%, respectively, and in 3 patients with the E2-146 variant, by 38%, 55%, 46%, and 35%, respectively. Simvastatin therapy lowered plasma activity of cholesteryl ester transfer protein but had no significant effect on plasma activity of lecithin:cholesterol acyltransferase. It is concluded that patients with FD due to various apoE variants have different lipoprotein profiles, mainly with regard to IDL and LDL levels, although they have a number of similar features of dysbetalipoproteinemia. Simvastatin therapy effectively reduced the plasma concentrations of total cholesterol, VLDL2 cholesterol, IDL cholesterol, and LDL cholesterol in the three groups of patients studied. It is proposed that apoE-dependent defects of the conversion of IDL to LDL may be an important mechanism in the pathophysiology of FD.

Adult↗
PubMed1994

Diet-induced hyperlipoproteinemia and atherosclerosis in apolipoprotein E3-Leiden transgenic mice.

Apolipoprotein E3-Leiden (APOE*3-Leiden) transgenic mice have been used to study the effect of different cholesterol-containing diets on the remnant lipoprotein levels and composition and on the possible concurrent development of atherosclerotic plaques. On high fat/cholesterol (HFC) diet, the high expressing lines 2 and 181 developed severe hypercholesterolemia (up to 40 and 60 mmol/liter, respectively), whereas triglyceride levels remained almost normal when compared with regular mouse diet. The addition of cholate increased the hypercholesterolemic effect of this diet. In lines 2 and 181, serum levels of apo E3-Leiden also increased dramatically upon cholesterol feeding (up to 107 and 300 mg/dl, respectively). In these high expressing APOE*3-Leiden transgenic mice, the increase in both serum cholesterol and apo E3-Leiden occurred mainly in the VLDL/LDL-sized fractions, whereas a considerable increase in large, apo E-rich HDL particles also occurred. In contrast to the high expressing lines, the low expressing line 195 reacted only mildly upon HFC diet. On HFC diets, the high expresser APOE*3-Leiden mice developed atherosclerotic lesions in the aortic arch, the descending aorta, and the carotid arteries, varying from fatty streaks containing foam cells to severe atherosclerotic plaques containing cholesterol crystals, fibrosis, and necrotic calcified tissue. Quantitative evaluation revealed that the atherogenesis is positively correlated with the serum level of cholesterol-rich VLDL/LDL particles. In conclusion, with APOE*3-Leiden transgenic mice, factors can be studied that influence the metabolism of remnant VLDL and the development of atherosclerosis.

Animals↗
PubMed1994

Variable expression of familial dysbetalipoproteinemia in apolipoprotein E*2 (Lys146-->Gln) Allele carriers.

Genetic and biochemical studies were carried out in 96 relatives of six independently ascertained probands with familial dysbetalipoproteinemia (FD) carrying the APOE*2 (Lys146-->Gln) allele. Compared to noncarriers, the 40 heterozygous APOE*2 (Lys146-->Gln) allele carriers exhibited markedly increased mean levels of cholesterol and triglyceride in the very low density lipoproteins (VLDL) (1.89 +/- 0.37 vs 0.30 +/- 0.27 and 1.86 +/- 0.37 vs 0.68 +/- 0.27 mmol/liter, respectively) and plasma apolipoprotein (apo) E levels (28.1 +/- 1.6 vs 4.6 +/- 1.1 mg/dl), which is characteristic for FD. By means of a pedigree-based maximum likelihood method we calculated that carrier-status accounted for 57% and 71%, respectively, of the total variance of the ratio (VLDL + IDL)-cholesterol/plasma triglyceride and plasma apoE levels. APOE*2 (Lys146-->Gln) and APOE*3-Leiden allele carriers were found to differ significantly in: (a) plasma apoE levels, (b) in the amounts of triglycerides in the VLDL and VLDL + IDL fraction, and (c) in the amount of cholesterol in the VLDL and VLDL + IDL fraction relative to the amount of triglyceride in these fractions. In the APOE*2 (Lys146-->Gln) allele carriers the VLDL and VLDL + IDL fraction is relatively rich in triglycerides as compared with that in APOE*3-Leiden carriers. We hypothesize that these two rare mutations of apoE both lead to dominantly inherited forms of FD along different underlying metabolic defects.

Adolescent↗
PubMed1993

Inefficient degradation of triglyceride-rich lipoprotein by HepG2 cells is due to a retarded transport to the lysosomal compartment.

Binding studies at 37 degrees C showed that lipoprotein lipase-treated very low density lipoproteins (LPL-VLDL) and very low density lipoproteins (VLDL), once taken up via the low density lipoprotein (LDL) receptor, are poorly degraded by HepG2 cells as compared with LDL. Determination of the initial endocytotic rate for LPL-VLDL and VLDL as compared to LDL shows that LPL-VLDL and VLDL are internalized at a similar rate as LDL. Incubation of cells with labeled LDL, LPL-VLDL, and VLDL at 18 degrees C for 4.5 h resulted in the accumulation of these particles in the early endosomes, without subsequent transport to the lysosomes and degradation. After washing the cells and a temperature shift to 37 degrees C, the labeled LDL present in the early endosomes is transported to the lysosomal compartment almost completely within 15 min. Strikingly, for LPL-VLDL and for VLDL, only about 50% or less of the label was moved to the lysosomal compartment within 45 min. However, once present in the lysosomes, VLDL and LPL-VLDL are degraded about 1.6-fold more rapidly than LDL. Retroendocytosis accounts for less than 10% of the internalized LDL, whereas a higher rate of retroendocytosis, up to 20 and 40%, respectively, was observed for LPL-VLDL and VLDL. To evaluate the effect of the inefficient transport of VLDL and LPL-VLDL to the lysosomal compartment on cellular cholesterol homeostasis, acyl-CoA:cholesterol acyltransferase (ACAT) activity was measured. Incubation with 30 micrograms/ml of LDL induced a 2.5-fold increase in ACAT activity, whereas the incubation with similar amounts of both VLDL and LPL-VLDL failed to stimulate this enzyme. We conclude that both a slower transport to the lysosomal compartment and a higher rate of retroendocytosis, possibly as the consequence of the longer residence time in the early endosomes, are responsible for the poor degradation of VLDL and LPL-VLDL by HepG2 cells.

Biological Transport↗
PubMed1993

A parent-twin study of plasma levels of histidine-rich glycoprotein (HRG).

Histidine-rich glycoprotein (HRG) is a non-enzymatic glycoprotein that acts as a modulator of several plasma proteins involved in coagulation and fibrinolysis. The contributions of genetic and environmental influences to inter-individual variation in plasma levels of HRG were studied in 160 Dutch families consisting of adolescent twin pairs and their parents. Results showed that 69% of the variance in plasma HRG concentrations could be accounted for by genetic factors. Heritability was the same in males and females and in parents and their offspring. There was no association between HRG levels of husband and wife and no evidence was found for the influence of shared family environment on the resemblance between relatives.

Adolescent↗
PubMed1993

Transgenic mice carrying the apolipoprotein E3-Leiden gene exhibit hyperlipoproteinemia.

Apolipoprotein (apo) E3-Leiden, described in a large Dutch family, is associated with a dominantly inherited form of familial dysbetalipoproteinemia. To study the effect of the APOE*3-Leiden mutation in vivo, transgenic mice were generated using a genomic 27-kilobase DNA construct isolated from the APOE*3-Leiden proband. This construct carried the APOE gene, the APOC1 gene, and all known regulatory elements including an element that mediates liver expression. Three strains were generated that showed human APOE and APOC1 expression. All strains had significantly elevated levels of total plasma cholesterol and triglycerides on a regular diet. When mice of one strain were fed a semisynthetic cholesterol-rich diet, total plasma cholesterol and triglyceride levels increased dramatically. This increase was observed mainly in the very low density lipoprotein (VLDL)- and low density lipoprotein (LDL)-sized fractions. In cholesterol-fed mice, the apoE3-Leiden protein became equally distributed between the VLDL/LDL and HDL-sized fractions, while in mice kept on a regular diet, apoE3-Leiden protein was mainly associated with HDL-sized fractions. The presence of hyperlipoproteinemia in the APOE*3-Leiden-expressing transgenic mice supports our finding that the apoE3-Leiden variant behaves like a dominant trait in the expression of familial dysbetalipoproteinemia. ApoE3-Leiden transgenic mice may serve as a model to elucidate additional factors involved in the metabolism of apoE containing remnant lipoproteins in general and the etiology of familial dysbetalipoproteinemia in particular.

Animals↗
PubMed1993

Low density lipoprotein receptor internalizes low density and very low density lipoproteins that are bound to heparan sulfate proteoglycans via lipoprotein lipase.

It has previously been shown that lipoprotein lipase (LPL) enhances the binding of low density lipoproteins (LDL) and very low density lipoproteins (VLDL) to HepG2 cells and fibroblasts, up to 80-fold. This increase in binding is LDL receptor-independent and is due to a bridging of LPL between extracellular heparan sulfate proteoglycans (HSPG) and the lipoproteins. In the present paper, we show that preincubation of the cells with LPL, followed by washing prior to the binding experiment, increased binding to the same extent as occurs when the binding is performed in the presence of LPL. This indicates that the formation of a complex of LPL with the lipoproteins is not a prerequisite of binding. Binding curves and Scatchard analyses reveal that both the number of binding sites and the affinity of the binding are increased 20-30-fold by the addition of 3.4 micrograms/ml LPL. The addition of LPL also resulted in an enhanced uptake and subsequent lysosomal degradation of both LDL and VLDL when compared with binding, although to a lesser extent (up to 25-fold when measured after 5 h at 37 degrees C). Strikingly, enhanced uptake did not occur in LDL receptor-negative fibroblasts. In addition, down-regulation of the LDL receptor activity by preincubation of the cells for 48 h with either LDL or beta-VLDL resulted in a parallel decrease in the uptake of LPL-mediated HSPG-bound LDL, whereas the LPL-mediated binding itself was not diminished. These observations indicate that the uptake of LPL-mediated HSPG-bound LDL and VLDL mainly proceeds via the LDL receptor. Binding of labeled LDL to the cells at 4 degrees C for 2 h followed by a chase period at 37 degrees C revealed that in absolute terms, the initial rate of internalization of HSPG-bound LDL is comparable with that of LDL receptor-bound LDL (0.58 and 0.44 ng/min/mg of cell protein, respectively). We conclude that in LDL receptor-positive cells, the LPL-mediated binding of LDL and VLDL to HSPG is followed by internalization of the lipoproteins mainly through the rapid process of the classical LDL receptor recycling system, whereas only a minor portion is internalized via the much slower process of HSPG uptake.

Animals↗
PubMed1993

The mouse low density lipoprotein receptor gene: cDNA sequence and exon-intron structure.

The low density lipoprotein (LDL) receptor plays a central role in the cholesterol metabolism. The cDNA sequence of the mouse low density lipoprotein receptor (Ldlr) gene has been determined and shows 76% homology with the human gene. The exon-intron structure has been determined for the 129/J mouse strain. The gene is composed of 18 exons and spans a region of 28 kb. In addition, the promoter regions of the mouse and human genes are homologous. Northern blot analysis revealed an mRNA of approximately 5 kb. The cloning of the Ldlr gene will enhance the usefulness of the mouse for the study of cholesterol metabolism and, in particular, for carrying out gene targeting experiments.

Amino Acid Sequence↗