Funke H

References (23)

Title : Heterozygosity for lysosomal acid lipase E8SJM mutation and serum lipid concentrations - Muntoni_2013_Nutr.Metab.Cardiovasc.Dis_23_732
Author(s) : Muntoni S , Wiebusch H , Jansen-Rust M , Rust S , Schulte H , Berger K , Pisciotta L , Bertolini S , Funke H , Seedorf U , Assmann G
Ref : Nutr Metab Cardiovasc Dis , 23 :732 , 2013
Abstract : BACKGROUND AND AIM: The complete absence of the lysosomal acid lipase (LAL) enzyme function causes Wolman's Disease that is fatal within the first six months of life. Subtotal defects cause Cholesteryl ester storage disease (CESD), an autosomal recessive disorder leading to hepatic steatosis, fibrosis, micronodular cirrhosis, combined hyperlipidemia with low HDL-cholesterol, increased risk for atherosclerosis, premature death. Since the frequency of the Exon 8 splice junction mutation (c.894 G > A, E8SJM), the CESD leading mutation, is not rare in the general population (allele frequency 0.0025), we investigated the impact of this mutation on serum lipid profile in E8SJM carriers. METHODS AND
RESULTS: We collected E8SJM carriers both form genetic study-population analysis and from Outpatient Lipid Clinics and then we assessed their serum lipid profile. We found thirteen individuals heterozygote for E8SJM. Most of them were Germans, three Spanish and two Italian. We found a significant increase in total cholesterol levels in both sexes with E8SJM mutation, leading to a significant increase in LDL cholesterol in males.
CONCLUSIONS: Our results show that LAL E8SJM carriers have an alteration in lipid profile with a Polygenic Hypercholesterolemia phenotype, leading to an increase in cardiovascular risk profile.
ESTHER : Muntoni_2013_Nutr.Metab.Cardiovasc.Dis_23_732
PubMedSearch : Muntoni_2013_Nutr.Metab.Cardiovasc.Dis_23_732
PubMedID: 22795295
Gene_locus related to this paper: human-LIPA

Title : Detection of missense mutations in the genes for lipoprotein lipase and hepatic triglyceride lipase in patients with dyslipidemia undergoing coronary angiography - Moennig_2000_Atherosclerosis_149_395
Author(s) : Moennig G , Wiebusch H , Enbergs A , Dorszewski A , Kerber S , Schulte H , Vielhauer C , Haverkamp W , Assmann G , Breithardt G , Funke H
Ref : Atherosclerosis , 149 :395 , 2000
Abstract : Coronary events have a close association with a low HDL/hypertriglyceridemia (LHDL/HTG) phenotype. As enzymes that hydrolyze triglyceride-rich lipoproteins are associated with a modulation of both HDL cholesterol and triglycerides, we have tested the hypothesis that mutations in the genes encoding lipoprotein lipase (LPL) or hepatic lipase (HTGL) may contribute to the formation of coronary atherosclerosis and, thus, of coronary heart disease (CHD). The entire coding and boundary regions of LPL and HTGL genes were analyzed by direct sequencing in 20 patients with both LHDL/HTG and diagnosed CHD. In the LPL gene six different polymorphisms were identified with same frequencies observed in the general population. In the HTGL gene, besides several polymorphisms, we identified three missense mutations: Asn37His, Val73Met, and Ser267Phe. Population screening using allele specific PCR identified Val73Met as a polymorphism while the two others were absent from 100 control individuals. One of the mutations (Ser267Phe) is known to cause HTGL deficiency and is associated with type III hyperlipoproteinemia. Since this dyslipoproteinemia meets the criteria of LHDL/HTG, it is intriguing to speculate that missense mutations in HTGL may play a role in the pathogenesis of this atherogenic phenotype.
ESTHER : Moennig_2000_Atherosclerosis_149_395
PubMedSearch : Moennig_2000_Atherosclerosis_149_395
PubMedID: 10729390

Title : Heterozygous hepatic lipase deficiency, due to two missense mutations R186H and L334F, in the HL gene - Knudsen_1997_Atherosclerosis_128_165
Author(s) : Knudsen P , Antikainen M , Uusi-Oukari M , Ehnholm S , Lahdenpera S , Bensadoun A , Funke H , Wiebusch H , Assmann G , Taskinen MR , Ehnholm C
Ref : Atherosclerosis , 128 :165 , 1997
Abstract : Hepatic lipase (HL) is an endothelial enzyme involved in the metabolism of intermediate density lipoproteins (IDL) and high density lipoproteins (HDL) in plasma. In a Finnish pedigree consisting of 18 members belonging to three generations two missense mutations RI86H and L334F in exons 5 and 7 of the HL gene co-segregated with low post-heparin HL activity. Haplotype analysis of the HL gene in family members revealed a high degree of genetic variation and demonstrated that the two missense mutations reside on the same chromosome. In vitro site-directed mutagenesis and expression of the cDNA constructs in COS-1 cells revealed that the R186H mutation leads to a protein that is not secreted while the L334F mutation results in the production of a HL protein that is secreted but has only about 30% of wild type HL activity. Carriers of the mutated HL gene exhibited clearly reduced HL activity and mass in post-heparin plasma. Probably due to their heterozygous carrier status they had only moderate elevation of total triglycerides, IDL, and LDL-triglycerides. The LDL-particles were enriched in triglycerides and depleted of cholesterol. Also their HDL2- and HDL3-particles were enriched in triglycerides.
ESTHER : Knudsen_1997_Atherosclerosis_128_165
PubMedSearch : Knudsen_1997_Atherosclerosis_128_165
PubMedID: 9050773
Gene_locus related to this paper: human-LIPC

Title : A novel missense mutation (Gly2Arg) in the human lysosomal acid lipase gene is found in individuals with and without cholesterol ester storage disease (CESD) -
Author(s) : Wiebusch H , Muntoni S , Funke H , Lu F , Seedorf U , Oberle S , Schwarzer U , Assmann G
Ref : Clin Genet , 50 :106 , 1996
PubMedID: 8937772

Title : An intronic mutation in a lariat branchpoint sequence is a direct cause of an inherited human disorder (fish-eye disease) - Kuivenhoven_1996_J.Clin.Invest_98_358
Author(s) : Kuivenhoven JA , Weibusch H , Pritchard PH , Funke H , Benne R , Assmann G , Kastelein JJ
Ref : J Clinical Investigation , 98 :358 , 1996
Abstract : The first step in the splicing of an intron from nuclear precursors of mRNA results in the formation of a lariat structure. A distinct intronic nucleotide sequence, known as the branchpoint region, plays a central role in this process. We here describe a point mutation in such a sequence. Three sisters were shown to suffer from fish-eye disease (FED), a disorder which is caused by mutations in the gene coding for lecithin:cholesterol acyltransferase (LCAT). Sequencing of the LCAT gene of all three probands revealed compound heterozygosity for a missense mutation in exon 4 which is reported to underlie the FED phenotype, and a point mutation located in intron 4 (IVS4:T-22C). By performing in vitro expression of LCAT minigenes and reverse transcriptase PCR on mRNA isolated from leukocytes of the patient, this gene defect was shown to cause a null allele as the result of complete intron retention. In conclusion, we demonstrated that a point mutation in a lariat branchpoint consensus sequence causes a null allele in a patient with FED. In addition, our finding illustrates the importance of this sequence for normal human mRNA processing. Finally, this report provides a widely applicable strategy which ensures fast and effective screening for intronic defects that underlie differential gene expression.
ESTHER : Kuivenhoven_1996_J.Clin.Invest_98_358
PubMedSearch : Kuivenhoven_1996_J.Clin.Invest_98_358
PubMedID: 8755645

Title : A missense mutation (Thr-6Pro) in the lysosomal acid lipase (LAL) gene is present with a high frequency in three different ethnic populations: impact on serum lipoprotein concentrations - Muntoni_1996_Hum.Genet_97_265
Author(s) : Muntoni S , Wiebusch H , Funke H , Seedorf U , Roskos M , Schulte H , Saku K , Arakawa K , Balestrieri A , Assmann G
Ref : Hum Genet , 97 :265 , 1996
Abstract : A frequent missense mutation (Thr-6Pro) found in the prepeptide of the lysosomal acid lipase (LAL) gene was analyzed in a cohort of 1003 randomly selected samples from Germany, Japan and Sardinia (Italy). Using the mutagenically separated polymerase chain reaction (MS-PCR), allele frequencies of 0.269, 0.238 and 0.245 were determined in the three populations, respectively. Statistical analysis showed a lack of association with a dyslipidemic phenotype in all three groups. Additionally, in a subgroup of 126 German individuals no association was observed between genotype and LAL activity. We conclude that this mutation appears to be a frequent LAL gene polymorphism causing no impaired function of the enzyme and no measurable dyslipidemia in the general population.
ESTHER : Muntoni_1996_Hum.Genet_97_265
PubMedSearch : Muntoni_1996_Hum.Genet_97_265
PubMedID: 8566968

Title : Complete deficiency of plasma lecithin-cholesterol acyltransferase (LCAT) activity due to a novel homozygous mutation (Gly-30-Ser) in the LCAT gene -
Author(s) : Owen JS , Wiebusch H , Cullen P , Watts GF , Lima VL , Funke H , Assmann G
Ref : Hum Mutat , 8 :79 , 1996
PubMedID: 8807342

Title : Compound heterozygosity for a known and a novel defect in the lipoprotein lipase gene (Asp250-->\;Asn\; Ser251-->\;Cys) resulting in lipoprotein lipase (LPL) deficiency - Bijvoet_1996_Neth.J.Med_49_189
Author(s) : Bijvoet SM , Wiebusch H , Ma Y , Reymer PW , Bruin T , Bakker HD , Funke H , Assmann G , Hayden MR , Kastelein JJ
Ref : Neth J Med , 49 :189 , 1996
Abstract : Two missense mutations in exon 6 of the LPL gene were identified on separate alleles in a Dutch patient with lipoprotein lipase (LPL) deficiency. The first mutation is a G1003-->A transition resulting in a D250N mutation, which has been shown previously to result in a catalytically defective protein in patients of French-Canadian ancestry. The second mutation, a C to G transition at nucleotide 1007, predicts a S251C residue change in the highly conserved region of LPL surrounding the loop structure the covers the catalytic triad. This mutation constitutes a novel defect among LPL gene mutations reported so far. Site-directed mutagenesis experiments provide in-vitro evidence for the complete loss of LPL activity resulting from this latter missense mutation. The G1003-->A nucleotide substitution underlying the Asp250 mutation deletes a TaqI endonuclease recognition site and the C1007-->G change that leads to the S251C alteration abolishes a HinfI recognition site. This will facilitate rapid screening for these mutations in LPL-deficient patients.
ESTHER : Bijvoet_1996_Neth.J.Med_49_189
PubMedSearch : Bijvoet_1996_Neth.J.Med_49_189
PubMedID: 8973094

Title : A new molecular defect in the lecithin: cholesterol acyltransferase (LCAT) gene associated with fish eye disease - Contacos_1996_J.Lipid.Res_37_35
Author(s) : Contacos C , Sullivan DR , Rye KA , Funke H , Assmann G
Ref : J Lipid Res , 37 :35 , 1996
Abstract : We report a new genetic defect in the lecithin:cholesterol acyltransferase (LCAT) gene associated with classical clinical and biochemical features of fish eye disease. The 63-year-old Australian female proband also suffers from non-insulin-dependent (type II) diabetes mellitus. She presented with corneal opacities, markedly reduced HDL-cholesterol (0.1 mmol/L; < 10% of normal controls), and elevated plasma triglycerides. The presence of diabetes did not explain the lipoprotein profile, which differed markedly in comparison to two female hypertriglyceridemic diabetic subjects. Cholesterol esterification in HDL-like particles was minimal but plasma cholesterol esterification was maintained due to LCAT activity in non-HDL-containing lipoprotein fractions. DNA sequence analysis of the proband's LCAT gene showed two C to T transitions resulting in the substitution of Thr123 with Ile and Tyr144 with Cys. Allele-specific PCR amplification procedures were used to confirm the presence of the mutations in this proband and to screen for additional carriers in her family. Three first degree relatives (mother, brother, son) were heterozygous for the Thr123 --> Ile mutation and her daughter had the Tyr144 --> Cys mutation. Apart from a reduction in HDL-cholesterol levels to half the normal concentration and a 20% reduction in apoA-I levels, their plasma lipids were unremarkable. The proband's son and daughter were further investigated. Both had normal cholesterol esterification rates in plasma and VLDL/LDL-depleted plasma, but reduced LCAT activity (50% that of normal). Thus, the biochemical and phenotypic expression for fish eye disease in the heterozygote subjects was similar, irrespective of the underlying LCAT mutation.
ESTHER : Contacos_1996_J.Lipid.Res_37_35
PubMedSearch : Contacos_1996_J.Lipid.Res_37_35
PubMedID: 8820100

Title : Compound heterozygosity for a known (D250N) and a novel (E410K) missense mutation in the C-terminal domain of lipoprotein lipase causes familial chylomicronemia -
Author(s) : Wiebusch H , Funke H , Bruin T , Bucher H , von Eckardstein A , Kastelein JJ , Assmann G
Ref : Hum Mutat , 8 :381 , 1996
PubMedID: 8956048
Gene_locus related to this paper: human-LPL

Title : A novel missense (E163G) mutation in the catalytic subunit of lipoprotein lipase causes familial chylomicronemia -
Author(s) : Wiebusch H , Funke H , Santer R , Richter W , Assmann G
Ref : Hum Mutat , 8 :392 , 1996
PubMedID: 8956052

Title : A novel variant of lysosomal acid lipase (Leu336-->\;Pro) associated with acid lipase deficiency and cholesterol ester storage disease - Seedorf_1995_Arterioscler.Thromb.Vasc.Biol_15_773
Author(s) : Seedorf U , Wiebusch H , Muntoni S , Christensen NC , Skovby F , Nickel V , Roskos M , Funke H , Ose L , Assmann G
Ref : Arterioscler Thromb Vasc Biol , 15 :773 , 1995
Abstract : Cholesterol ester storage disease (CESD) is associated with premature atherosclerosis, hepatomegaly, elevated LDL cholesterol levels, and in most cases, low HDL cholesterol levels. Previous studies have shown a G-->A mutation at the 3' splice junction of exon 8 (E8SJM) of the gene encoding lysosomal acid lipase (LAL) in two kindreds with CESD. In a Canadian-Norwegian kindred with this disease, we show this mutation in conjunction with an as yet unknown T-->C transition in exon 10 predicting a Leu336-->Pro (L336P) replacement and an A-->C transversion in exon 2 predicting a T-6P replacement in the prepeptide. Identification of the L336P rather than the T-6P replacement as the second defect underlying CESD in our patient is deduced from three lines of evidence. First, the E8SJM allele is located in cis with the mutation predicting the T-6P-encoding allele but in trans with the L336P-encoding allele; second, the L336P but not the T-6P replacement cosegregates with low LAL activity in the family; third, the T-6P replacement was found in 6 of 28 alleles from subjects with normal lysosomal acid lipase activity, suggesting that this variant represents a frequent nonfunctional polymorphism. Since the residual LAL activity is higher and the clinical phenotype based on plasma lipid values and severity of hepatosplenomegaly is milder in this case than in a previously studied case who was homozygous for the E8SJM allele, we conclude that the L336P variant appears to be associated with a phenotypically mild form of CESD.
ESTHER : Seedorf_1995_Arterioscler.Thromb.Vasc.Biol_15_773
PubMedSearch : Seedorf_1995_Arterioscler.Thromb.Vasc.Biol_15_773
PubMedID: 7773732
Gene_locus related to this paper: human-LIPA

Title : A unique genetic and biochemical presentation of fish-eye disease - Kuivenhoven_1995_J.Clin.Invest_96_2783
Author(s) : Kuivenhoven JA , van Voorst tot Voorst EJ , Wiebusch H , Marcovina SM , Funke H , Assmann G , Pritchard PH , Kastelein JJ
Ref : J Clinical Investigation , 96 :2783 , 1995
Abstract : This paper describes a novel genetic defect which causes fish-eye disease in four homozygous probands and its biochemical presentation in 34 heterozygous siblings. The male index patient presented with premature coronary artery disease, corneal opacification, HDL deficiency, and a near total loss of plasma lecithin:cholesterol acyltransferase (LCAT) activity. Sequencing of the LCAT gene revealed homozygosity for a novel missense mutation resulting in an Asp131 - Asn (N131D) substitution. Heterozygotes showed a highly significant reduction of HDL-cholesterol and apolipoprotein A-I levels as compared with controls which was associated with a specific decrease of LpA-I:A-II particles. Functional assessment of this mutation revealed loss of specific activity of recombinant LCAT(N131D) against proteoliposomes. Unlike other mutations causing fish-eye disease, recombinant LCAT(N131D) also showed a 75% reduction in specific activity against LDL. These unique biochemical characteristics reveal the heterogeneity of phenotypic expression of LCAT gene defects within a range specified by complete loss of LCAT activity and the specific loss of activity against HDL. The impact of this mutation on HDL levels and HDL subclass distribution may be related to the premature coronary artery disease observed in the male probands.
ESTHER : Kuivenhoven_1995_J.Clin.Invest_96_2783
PubMedSearch : Kuivenhoven_1995_J.Clin.Invest_96_2783
PubMedID: 8675648

Title : Homozygosity for a splice junction mutation in exon 8 of the gene encoding lysosomal acid lipase in a Spanish kindred with cholesterol ester storage disease (CESD) - Muntoni_1995_Hum.Genet_95_491
Author(s) : Muntoni S , Wiebusch H , Funke H , Ros E , Seedorf U , Assmann G
Ref : Hum Genet , 95 :491 , 1995
Abstract : Deficiency of lysosomal acid lipase is expressed in two distinct recognizable phenotypes. Wolman disease represents the severe early onset form, whereas cholesterol ester storage disease is the more benign late onset type. Previous studies have indicated that compound heterozygosity consisting of a G-->A mutation at the 3'-splice junction of exon 8 (E8SJM-allele) together with a null allele of the gene encoding lysosomal acid lipase leads to cholesterol ester storage disease. We have now observed homozygosity for the G-->A splice junction mutation in a non-related Spanish kindred with the same disease. As expected, the residual activity of lysosomal acid lipase is higher in this case, suggesting that the E8SJM-allele is associated with low residual acid lipase activity. However, the phenotype of the homozygous propositus is more severe compared with the previously described case, indicating that no direct relationship exists between the genotype or residual LAL activity and the precise cholesterol or triglyceride levels in a given patient. Nevertheless, our findings provide convincing evidence that homozygosity for the E8SJM-allele causes cholesterol ester storage disease to at least the same extent as compound heterozygosity consisting of this allele and a null allele.
ESTHER : Muntoni_1995_Hum.Genet_95_491
PubMedSearch : Muntoni_1995_Hum.Genet_95_491
PubMedID: 7759067

Title : Deficiency of lecithin:cholesterol acyltransferase due to compound heterozygosity of two novel mutations (Gly33Arg and 30 bp ins) in the LCAT gene -
Author(s) : Wiebusch H , Cullen P , Owen JS , Collins D , Sharp PS , Funke H , Assmann G
Ref : Hum Mol Genet , 4 :143 , 1995
PubMedID: 7711728
Gene_locus related to this paper: human-LCAT

Title : Recurrent missense mutations at the first and second base of codon Arg243 in human lipoprotein lipase in patients of different ancestries - Ma_1994_Hum.Mutat_3_52
Author(s) : Ma Y , Liu MS , Chitayat D , Bruin T , Beisiegel U , Benlian P , Foubert L , De Gennes JL , Funke H , Forsythe I , Blaichman S , Papanikolaou M , Erkelens DW , Kastelein J , Brunzell JD , Hayden MR
Ref : Hum Mutat , 3 :52 , 1994
Abstract : Mutations in the lipoprotein lipase (LPL) gene are the most common cause of familial chylomicronemia. Here we define the molecular basis of LPL deficiency in four patients of German, French, Dutch, and Chinese descent. We show that two of the probands of Dutch and Chinese origin have a previously described Arg243His mutation while the patients of German and French descent have a novel Arg243Cys substitution in their LPL gene. Haplotype analysis is in favour of two separate origins for the Arg243Cys substitution which together with the Arg243His mutation would implicate three recurrent mutations involving the first and second nucleotides of the codon encoding Arg243 of the LPL gene. The recurrent mutations affecting the first and second nucleotide of CGC coding for the normal Arg residue are support for the high mutability of CpG dinucleotides within the LPL gene.
ESTHER : Ma_1994_Hum.Mutat_3_52
PubMedSearch : Ma_1994_Hum.Mutat_3_52
PubMedID: 7906986

Title : Phenotypic variation of mutations in the human lipoprotein-lipase gene - Hayden_1993_Biochem.Soc.Trans_21_506
Author(s) : Hayden MR , Kastelein JJ , Funke H , Brunzell JD , Ma Y
Ref : Biochemical Society Transactions , 21 :506 , 1993
Abstract : We have described a large number of different mutations in the LPL gene that result in completely catalytically defective LPL protein. More recently exonic polymorphisms in the LPL gene have been described that do not result in the catalytic activity of LPL being significantly impaired. Furthermore we have recently described a patient who is homozygous for a mutation in the LPL gene in a conserved region of exon 5 that results only in partial residual activity and a very mild clinical phenotype. This may suggest that the frequency of mutations in the LPL gene is greater than has been previously recognized. Recognition and selection of patients for analysis was based on the phenotype of chylomicronaemia. However, the existence of the Ser172-Cys mutation in the LPL gene that results in only moderate hypertriglyceridaemia in the absence of environmental factors might suggest that mutations in this gene are more frequent and could be seen in patients with a milder clinical phenotype. The clue to detecting these changes in the LPL gene might be to investigate patients who present with chylomicronaemia due to different environmental triggers while, in the absence of these environmental factors, they have only moderate hypertriglyceridaemia.
ESTHER : Hayden_1993_Biochem.Soc.Trans_21_506
PubMedSearch : Hayden_1993_Biochem.Soc.Trans_21_506
PubMedID: 8359520

Title : Genetic and phenotypic heterogeneity in familial lecithin: cholesterol acyltransferase (LCAT) deficiency. Six newly identified defective alleles further contribute to the structural heterogeneity in this disease - Funke_1993_J.Clin.Invest_91_677
Author(s) : Funke H , von Eckardstein A , Pritchard PH , Hornby AE , Wiebusch H , Motti C , Hayden MR , Dachet C , Jacotot B , Gerdes U , Faergeman O , Albers JJ , Colleoni N , Catapano A , Frohlich J , Assmann G
Ref : J Clinical Investigation , 91 :677 , 1993
Abstract : The presence of lecithin:cholesterol acyltransferase (LCAT) deficiency in six probands from five families originating from four different countries was confirmed by the absence or near absence of LCAT activity. Also, other invariate symptoms of LCAT deficiency, a significant increase of unesterified cholesterol in plasma lipoproteins and the reduction of plasma HDL-cholesterol to levels below one-tenth of normal, were present in all probands. In the probands from two families, no mass was detectable, while in others reduced amounts of LCAT mass indicated the presence of a functionally inactive protein. Sequence analysis identified homozygous missense or nonsense mutations in four probands. Two probands from one family both were found to be compound heterozygotes for a missense mutation and for a single base insertion causing a reading frame-shift. Subsequent family analyses were carried out using mutagenic primers for carrier identification. LCAT activity and LCAT mass in 23 genotypic heterozygotes were approximately half normal and clearly distinct from those of 20 unaffected family members. In the homozygous patients no obvious relationship between residual LCAT activity and the clinical phenotype was seen. The observation that the molecular defects in LCAT deficiency are dispersed in different regions of the enzyme suggests the existence of several functionally important structural domains in this enzyme.
ESTHER : Funke_1993_J.Clin.Invest_91_677
PubMedSearch : Funke_1993_J.Clin.Invest_91_677
PubMedID: 8432868
Gene_locus related to this paper: human-LCAT

Title : Molecular basis of lipoprotein lipase deficiency in two Austrian families with type I hyperlipoproteinemia - Paulweber_1991_Atherosclerosis_86_239
Author(s) : Paulweber B , Wiebusch H , Miesenboeck G , Funke H , Assmann G , Hoelzl B , Sippl MJ , Friedl W , Patsch JR , Sandhofer F
Ref : Atherosclerosis , 86 :239 , 1991
Abstract : To determine the molecular basis for type I hyperlipoproteinemia in two Austrian families, the lipoprotein lipase (LPL) gene of two patients exhibiting LPL deficiency was analyzed by Southern blotting and by direct genomic sequencing of DNA amplified by polymerase chain reaction (PCR). All exons of the LPL gene except part of the noncoding region of exon 10, all splice donor and acceptor sites, as well as 430 basepairs of the 5'-region including the promotor were sequenced. A homozygous substitution of adenine for guanine in the fifth exon at cDNA position 818 of the LPL gene was found in both patients. Our sequencing strategy largely ruled out a linkage disequilibrium of the identified nucleotide change with another defect potentially causing the clinical phenotype. The base change described abolishes a normally present AvaII restriction site allowing the identification of carriers of the mutant allele by AvaII digestion of PCR fragments of exon 5; three members of the two families were homozygous for this mutation and ten members were heterozygous. The activity of LPL in postheparin plasma was almost completely absent in homozygotes and about half normal in heterozygotes. The loss of activity was related to LPL protein structure. This mutation alters the amino acid sequence at residue 188 from Gly to Glu. The conformational preferences of the protein chain around position 188 were calculated with the use of a knowledge-based computerized method. The most probable conformation is a beta-turn formed by residues 189-192. The mutation seems to destabilize the beta-turn and/or a yet larger domain critical for substrate alignment.
ESTHER : Paulweber_1991_Atherosclerosis_86_239
PubMedSearch : Paulweber_1991_Atherosclerosis_86_239
PubMedID: 1872917

Title : Lecithin:cholesterol acyltransferase deficiency and fish eye disease. - Assmann_1991_Curr.Opin.Lipidol_2_110
Author(s) : Assmann G , von Eckardstein A , Funke H
Ref : Curr Opin Lipidol , 2 :110 , 1991
Abstract : Familial lecithin: cholesterol acyltransferase (LCAT) deficiency and fish-eye disease are rare autosomal recessively inherited disorders, which have in common severely reduced plasma concentrations of high-density lipoprotein cholesterol. Although both conditions originate from defects at the LCAT gene, their clinical and biochemical phenotypic expression is highly variable, presumably because of differently impaired activities and/or substrate specifities within the enzyme.
ESTHER : Assmann_1991_Curr.Opin.Lipidol_2_110
PubMedSearch : Assmann_1991_Curr.Opin.Lipidol_2_110

Title : A molecular defect causing fish eye disease: an amino acid exchange in lecithin-cholesterol acyltransferase (LCAT) leads to the selective loss of alpha-LCAT activity - Funke_1991_Proc.Natl.Acad.Sci.U.S.A_88_4855
Author(s) : Funke H , von Eckardstein A , Pritchard PH , Albers JJ , Kastelein JJ , Droste C , Assmann G
Ref : Proc Natl Acad Sci U S A , 88 :4855 , 1991
Abstract : Epidemiological as well as biochemical evidence of recent years has established that a low plasma level of high density lipoprotein-cholesterol is a predictor for the risk of coronary artery disease. However, there is a heterogeneous group of rare familial disorders, characterized by severe high density lipoprotein deficiency, in which the predicted increased risk is not clearly apparent. One such disorder has been called fish eye disease to reflect the massive corneal opacification seen in these patients. In this report, we describe the biochemical and genetic presentation of two German fish eye disease homozygotes and their family members. Vertical transmission of a decrease in the specific activity of lecithin-cholesterol acyltransferase (EC indicated that this enzyme was a candidate gene for harboring the defect responsible for this disorder. Direct sequencing of DNA segments amplified by the polymerase chain reaction (PCR) that encode the exons of the lecithin-cholesterol acyltransferase gene led to the identification of a homozygous mutation resulting in the substitution of threonine at codon 123 for an isoleucine residue in both individuals. Family analysis in an extended pedigree was used to establish a causal relationship between this mutation and the biochemical phenotype for fish eye disease. The homozygous presence of this mutation in two phenotypically homozygous members of an unrelated Dutch family with fish eye disease further supports this finding.
ESTHER : Funke_1991_Proc.Natl.Acad.Sci.U.S.A_88_4855
PubMedSearch : Funke_1991_Proc.Natl.Acad.Sci.U.S.A_88_4855
PubMedID: 2052566

Title : Bst NI (Eco RII) RFLP in the lipoprotein lipase gene (LPL) -
Author(s) : Funke H , Reckwerth A , Stapenhorst D , Schulze Beiering M , Jansen M , Assmann G
Ref : Nucleic Acids Research , 16 :2741 , 1988
PubMedID: 2896338

Title : Hind III RFLP in the lipoprotein lipase gene, (LPL) -
Author(s) : Funke H , Klug J , Assmann G
Ref : Nucleic Acids Research , 15 :9102 , 1987
PubMedID: 2891110