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Biomedical subjects

H Tenkanen

Publications and source records attributed to H Tenkanen.

13 recordsLinked to original sources
PubMed1996

Heterozygosity for Asn291-->Ser mutation in the lipoprotein lipase gene in two Finnish pedigrees: effect of hyperinsulinemia on the expression of hypertriglyceridemia.

We describe two Finnish kindreds with the Asn291 --> Ser mutation (A291S) of the lipoprotein lipase (LPL) gene. Sixteen subjects (9 male, 7 female) heterozygous for this mutation were studied and compared with 17 unaffected family members or spouses (family controls) and 19 unrelated healthy subjects (population controls). In the group of subjects heterozygous for the A291S mutation, postheparin plasma LPL activity was on average 23% lower than in the family controls and 29% lower than in the population controls. In agreement, in vitro expression studies with COS-7 cells showed that the mutant protein exhibits approximately 50% of the lipolytic activity of the wild-type protein. Median serum triglyceride concentration was 2.90 mmol/l in the group of heterozygotes, compared with 1.14 mmol/l in the family controls (P < 0.01) and 0.99 mmol/l in the population controls (P < 0.001). The heterozygotes also had a marked preponderance of small dense low density lipoproteins (LDL) as assessed by gradient gel electrophoresis. Nine of the heterozygous subjects were hypertriglyceridemic (serum triglyceride concentration > 2.0 mmol/l). Age or body mass index were not related to the presence of hypertriglyceridemia. By contrast, all hypertriglyceridemic subjects were either hyperinsulinemic (serum insulin concentration > 10 mU/l, n = 7) or had diabetes (n = 2). In a multivariate regression analysis, very low density lipoprotein (VLDL) triglyceride level was significantly and independently related to serum apolipoprotein B concentration, the presence of the A291S mutation, serum insulin concentration, and postheparin plasma LPL activity. The Asn291-->Ser mutation of the LPL gene results in reduced lipolytic activity. However, dyslipidemia appears to manifest only if VLDL production is also increased. Hyperinsulinemia was the major determinant of excessive VLDL synthesis and dyslipidemia among the subjects heterozygous for the A291S mutation in this study.

Adolescent↗
PubMed1996

A compound heterozygote for hepatic lipase gene mutations Leu334-->Phe and Thr383-->Met: correlation between hepatic lipase activity and phenotypic expression.

We have characterized the molecular basis for familial hepatic lipase (HL) deficiency in a Finnish family. In the propositus, the HL deficiency results from compound heterozygosity for two rare HL gene mutations, a previously unknown missense mutation designated L334F and the previously reported T383M mutation. These mutations were introduced into human HL cDNA by site-directed mutagenesis and the constructs expressed in COS-1 cells. In the homogenate of COS-1 cell transfected with the L334F mutant cDNA, a high amount of inactive protein accumulated. In the media of L334F transfected cells, 30% of the wild type activity and 80% of wild type mass were detected. The lysates of COS-1 cells transfected with the T383M mutant cDNA contained 39% of wild type HL activity and 34% of wild type HL mass. In the media of COS-1 cells transfected with the T383M cDNA construct, 50% of wild type HL mass but only 6% of wild type activity was present. The single amino acid substitutions present in L334F and T383M are therefore sufficient to severely affect the HL enzyme. These defects explain the HL-deficient phenotype of the individual carrying the two mutations. The lipoprotein phenotype associated with compound heterozygosity for L334F and T383M mutations is characterized by a slight increase in the buoyant low density lipoprotein (LDL) fraction and an increase in the light high density lipoprotein (HDL) fractions, HDL2a and HDL2b. These results demonstrate that lipoprotein changes occurring in HL deficiency are difficult to identify and support the hypothesis that HL is important in HDL remodeling and metabolism in vivo.

Adult↗
PubMed1994

Genetic polymorphism of apolipoprotein A-IV in five different regions of Europe. Relations to plasma lipoproteins and to history of myocardial infarction: the EARS study. European Atherosclerosis Research Study.

As a part of the EARS study we assessed the role of the common apo A-IV polymorphism in determining the hereditary predisposition to cardiovascular disease. The study population consisted of 1261 controls and 629 cases (students whose father had MI before 55 years) from five different European regions. The apo A-IV 1-1 phenotype accounted for 85% of the individuals. One per cent of subjects were homozygous for the apo A-IV2 allele. There was significant regional variation in the apo A-IV allele frequencies from North to South in Europe, with the lowest A-IV2 frequency in Finland. The distribution of the apo A-IV phenotypes was similar in cases and controls, as was the regional variation. The apo A-IV polymorphism did not affect HDL cholesterol. There was no correlation between apo A-IV alleles and the plasma concentration of apo A-IV. The plasma concentration of apo A-IV was lower in females than in males; furthermore, there was a significant difference in apo A-IV concentrations between oral contraceptive users and nonusers: users had the lowest values. As no strongly significant genetic difference could be demonstrated between plasma lipid concentration in cases and controls, and as the apo A-IV polymorphism did not significantly influence plasma lipid concentration, we conclude that the apo A-IV gene is not a major determinant of the risk for MI and/or CHD.

Adolescent↗
PubMed1994

A novel amino acid substitution (His183-->Gln) in exon 5 of the lipoprotein lipase gene results in loss of catalytic activity: phenotypic expression of the mutant gene in a heterozygous state.

We have identified a hitherto unrecognized mutation of the lipoprotein lipase gene (LPL) in a Finnish family with Russian and Swiss ancestors. A single base pair substitution of a guanine for cytosine in codon 183 of exon 5 of the LPL gene results in a change of histidine to glutamine in the mature enzyme protein. Expression of a mutant cDNA construct in COS cells resulted in secretion of inactive LPL enzyme protein confirming the functional significance of the mutation. The proband, a 50-year-old female and her two daughters were all heterozygous for the His183-->Gln mutation. Clinically, the proband was characterized by variable and occasionally severe hypertriglyceridemia, obesity, hypertension, coronary heart disease and non-insulin-dependent diabetes mellitus. The daughters, aged 24 and 19 years, were also obese but had milder hypertriglyceridemia. In conclusion, we have identified a novel LPL mutation that results in the synthesis of an inactive enzyme protein. Although the assessment of a causative link between the mutation and hyperlipidemia awaits further studies, our data suggest that heterozygosity for a functional defect of LPL should be considered in patients presenting with the metabolic dyslipidemic syndrome, "syndrome-X."

Amino Acids↗
PubMed1992

Studies on the proteins involved in the interaction of high-density lipoprotein with isolated human small intestine epithelial cells.

Treatment of 125I-labelled high-density lipoprotein ([125I]HDL3) with monospecific polyclonal antibodies against apolipoproteins A-I and A-II resulted in a dose-dependent inhibition of the [125I]HDL3 binding to isolated human small intestine epithelial cells by 25% and 50%, respectively. Both antibodies also inhibited intracellular degradation of [125I]HDL3 by 80%. Treatment of enterocytes with polyclonal antibody against apolipoprotein A-I binding protein, a putative HDL receptor, inhibited both binding and degradation of [125I]HDL3 by these cells by 50%. Antibodies to apolipoprotein A-I, A-II and apo A-I-binding protein also inhibited [125I]HDL3 binding to cholesterol-loaded cells.

Antibodies↗
PubMed1992

A novel polymorphism of apolipoprotein A-IV is the result of an asparagine to serine substitution at residue 127.

We have identified a hitherto unknown genetic polymorphism of apolipoprotein A-IV (apoA-IV). The molecular basis for this polymorphism is an A to G substitution at nucleotide 1687 resulting in an Asn to Ser change of amino acid 127. The frequencies of the two apoA-IV alleles (designated apoA-IV127Asn and apoA-IV127Ser), determined by Hin c II restriction analysis of PCR amplified exon three of the apoA-IV gene, were 0.788 and 0.212, respectively, in a Finnish population sample. Allele frequencies of another polymorphism due to a Thr to Ser substitution at amino acid 347 were determined using Hinf I restriction analysis. The allele frequencies were 0.823 for apoA-IV347Thr and 0.177 for apoA-IV347Ser. None of the apoA-IV polymorphisms (apoA-IV127:Asn----Ser, apoA-IV347:Thr----Ser and apoA-IV360:Gln----His) had any effect on plasma lipid and lipoprotein concentrations in cohorts of dyslipidemic men and in a population sample of normolipidemic controls. There was also no association between the history of previous myocardial infarction and any of the apoA-IV alleles.

Alleles↗
PubMed1992

Molecular basis for apo A-IV polymorphisms.

Apolipoprotein (apo) A-IV is involved in the metabolism of triglyceride-rich lipoproteins and high-density lipoproteins and may thus play an important role in lipid metabolism, although the precise physiological function of apo A-IV is unknown. Structural and functional alterations of apolipoproteins, caused by a variety of mutations, have been shown to influence lipoprotein metabolism in several ways. Genetic studies are consistent with a single locus for apo A-IV with two main codominant alleles A-IV1 and A-IV2. The basis behind some of these electrophoretic variants has been determined on a molecular level by the aid of the polymerase chain reaction and sequencing of the amplified DNA. For instance, apo A-IV1 and apo A-IV2 alleles are explained by glutamine for histidine change of amino acid 360. Furthermore, several polymorphisms not leading to charge differences have been characterized. The genetic variability of apo A-IV may be of help in elucidating the functional role of apo A-IV in lipoprotein metabolism. In our study, the frequencies of the alleles due to Gln360-->His and Thr347-->Ser substitutions in a Finnish population sample were similar to those reported from other populations. In addition we have identified a novel genetic polymorphism of apo A-IV, Asn127-->Ser. In the Finnish population the asparagine for serine change of amino acid 127 was the most common apo A-IV polymorphism. There are no reports from other populations concerning this polymorphism.(ABSTRACT TRUNCATED AT 250 WORDS)

Alleles↗
PubMed1991

The apolipoprotein A-I binding protein of placenta and the SP-40,40 protein of human blood are different proteins which both bind to apolipoprotein A-I.

A complement-associated protein SP-40,40, which is a normal constituent of human blood, binds to the main apoprotein, apoA-I, of high density lipoprotein (HDL). This protein, which is identical to apolipoprotein J, was compared to another apoA-I binding protein purified from human placenta. Immunologically the two apoA-I binding proteins are different.

Amino Acid Sequence↗
PubMed1991

Polymorphisms of the gene encoding cholesterol ester transfer protein and serum lipoprotein levels in subjects with and without coronary heart disease.

We determined TaqI-A, TaqI-B and EcoNI genotypes at the cholesteryl ester transfer protein (CETP) locus in 111 healthy volunteers and in 187 hyperlipidemic men of whom 72 had suffered a myocardial infarction. There were no significant differences in the allele distributions at these polymorphic loci either between the population sample and the hyperlipidemic subjects, or between patients with and without previous myocardial infarction. To detect the associations between the CETP polymorphisms and serum lipid and apoprotein levels, we determined the serum concentrations of total cholesterol, triglycerides, high density lipoprotein (HDL)-cholesterol, apoA-I, apoA-II and apoB in the subjects studied and correlated them to the 3 RFLPs. No significant differences were observed in the serum levels of apoproteins and lipid parameters between subjects with different genotypes in any of these polymorphic CETP loci, either in the population sample or in hyperlipidemic men. Multivariate analyses did not reveal a significant independent role for any of the 3 polymorphisms in determining serum HDL-cholesterol or apoA-I levels after adjusting for triglyceride and low density lipoprotein cholesterol concentrations. This was evident for the group of healthy volunteers and for hyperlipidemic subjects, including those who had survived a myocardial infarction. We conclude that, in Finns, the CETP RFLPs are not useful markers for the risk of coronary heart disease.

Adult↗
PubMed1991

Genotyping of apolipoprotein A-IV by digestion of amplified DNA with restriction endonuclease Fnu4HI: use of a tailored primer to abolish additional recognition sites during the gene amplification.

Apolipoprotein A-IV (apoA-IV) is involved in the metabolism of chylomicrons and high density lipoproteins. It displays genetic polymorphism due to two co-dominant alleles apoA-IV1 and apoA-IV2. The mutation that causes the polymorphism is a G to T substitution in the third base of codon 360 in the apoA-IV2 allele which results in a glutamine (Gln) to histidine (His) change of amino acid 360. This substitution leads to the abolition of a recognition site for the restriction enzyme Fnu4HI. Part of the third exon of the apoA-IV gene is amplified by the polymerase chain reaction (PCR) using a tailored primer, which abolishes the downstream recognition sites during the DNA amplification. The PCR products are digested with the restriction enzyme Fnu4HI and electrophoresed on a polyacrylamide gel. The apoA-IV genotypes are determined after staining with either ethidium bromide or silver. To validate the method, we determined the inheritance of the apoA-IV alleles in a three-generation kindred of 8 subjects and analyzed amplified DNA of 32 subjects of different apoA-IV phenotypes with this method. The results were compared to those obtained from isoelectric focusing and immunoblotting. In all cases studied, the two methods gave concordant results.

Apolipoproteins A↗
PubMed1989

Transferrin C subtype frequencies in the Finnish population.

Transferrin (Tf) C subtypes were determined in 419 unrelated adult Finns. The calculated gene frequencies were C1 = 0.738, C2 = 0.097 and C3 = 0.133. The Tf phenotypes in 150 mother-child pairs were in accordance with autosomal codominant inheritance. This material included a rare TfC allele product in three individuals, apparently the same in all cases.

Adult↗
PubMedDate not supplied

The mutation causing the common apolipoprotein A-IV polymorphism is a glutamine to histidine substitution of amino acid 360.

Apolipoprotein (apo) A-IV is a protein involved in the metabolism of chylomicrons and high density lipoproteins. This protein displays genetic polymorphism due to two main codominant alleles, A-IV1 and A-IV2. We have identified the mutation that leads to this polymorphism. It is caused by a single-base substitution of guanine for thymine in the third base of codon 360. This substitution leads to a glutamine to histidine change. Direct sequencing of amplified DNA from eight subjects in a three-generation pedigree has demonstrated that the guanine to thymine substitution can explain the apo A-IV polymorphism. In 32 unrelated individuals, a correspondence between apo A-IV phenotype determined by isoelectric focusing and genotype determined with Fnu4HI digestion of amplified DNA could be demonstrated. The enzyme lecithin:cholesteryl acyltransferase (LCAT) is activated by apo A-IV. Under our in vitro conditions, the isoprotein apo A-IV 1-1 is a better LCAT activator than is the isoprotein apo A-IV 2-2. A knowledge of the molecular mechanism underlying the apo A-IV polymorphism will help to elucidate the mechanisms involved in LCAT activation.

Amino Acid Sequence↗