1/10. Two Italian kindreds carrying the Arg136-->Ser mutation of the Apo E gene: development of premature and severe atherosclerosis in the presence of epsilon 2 as second allele.BACKGROUND AND AIMS: Type III hyperlipoproteinemia, or dysbetalipoproteinemia, is commonly associated with apolipoprotein e2 homozygosity (Cys112, Cys158). Apo E2-Christchurch (Arg136-->Ser), a rare mutation of the Apo E gene, located in the receptor-binding domain of the protein, has been found to be associated in the vast majority of cases of dysbetalipoproteinemia. methods AND RESULTS: This is the first report of two Italian kindreds carrying the Arg136-->Ser mutation. One family is a four-generation kindred from Genoa (Liguria, italy) with a high rate of mortality due to coronary artery disease: the proband was a 51-year-old woman with previous myocardial infarction and residual angina, severe carotid atherosclerosis, peripheral arterial vascular disease and arterial hypertension. The other family was identified in Palermo (sicily, italy): the proband was an overweight 62-year-old man with a mixed form of hyperlipidemia. The mutation, which was identified by means of Apo E genotyping followed by direct sequencing, co-segregated with the same haplotype in the two families. CONCLUSIONS: The family histories and clinical examinations of these subjects clearly show that the Apo E Arg136-->Ser variant fully expresses a type III phenotype in association with a second allele coding for Apo E2, and only partially in association with a second allele coding for Apo E4.- - - - - - - - - - ranking = 1keywords = family (Clic here for more details about this article) |
2/10. Apolipoprotein E1 Lys-146Glu with type III hyperlipoproteinemia. During the screening of samples obtained from 5 individuals with type III hyperlipidemia, we identified a variant of apolipoprotein (apo) E which exhibited a discrepancy in apo E phenotype showing the E3/E1 isoform on isoelectric focusing (IEF) analysis and E3/E3 on gene analysis. sequence analysis of the dna of the proband that was amplified by PCR and subcloned, revealed a single substitution of one lysine (AAG) for one glutamic acid (GAG) at position 146, thereby adding two negatively charged units to apo E3. This defect had been described only for apo E1 to date (Mann et al. (1989) Clin. Res. 37, 520A (abstract)). In this case, PCR-mediated site-directed mutagenesis was used to identify the structural alterations forming the abnormal E1 genotype in the proband's family. Purified apo E1 Lys-146 Glu showed less than 10% of binding activity to apo B, E receptor on human skin fibroblasts compared with apo E3. This substitution demonstrates that Lys-146 is essential for the binding of apo E to the receptor.- - - - - - - - - - ranking = 0.33333333333333keywords = family (Clic here for more details about this article) |
3/10. Severe type III hyperlipoproteinemia associated with unusual apolipoprotein E1 phenotype and epsilon 1/'null' genotype.A 60-year-old white male (KH) was diagnosed to suffer from severe type III hyperlipoproteinemia (HLP) and premature cardiovascular disease. Biochemical analysis revealed an unusual apolipoprotein (apo) E phenotype and genotype. All clinical characteristics of type III HLP were present in the patient. His very low density lipoprotein (VLDL) cholesterol to plasma triglyceride (TG) ratio was elevated at 0.97 without therapy which is unusually high (normal ratio about 0.18). By contrast his plasma apo E level was only moderately elevated (6.8 mg dl-1). The patient's apo E migrated in the apo E1 position on isoelectric focusing gels. Chemical modification with cysteamine and treatment with neuraminidase confirmed the presence of two cysteine residues in the patient's apo E and a normal sialylation pattern. pedigree analysis suggested that the patient was a compound heterozygote with one apo epsilon 1 allele and another allele whose product did not appear in the plasma compartment ('null' allele). Direct sequencing of polymerase chain reaction (PCR) amplified segments of the apo E gene as well as restriction fragment length polymorphism (RFLP) analysis with the endonuclease Taq I identified an adenosine for guanosine (G-->A) exchange in the second base of codon 127 that is predictive for an Asp for Gly substitution in the encoded apo E amino acid sequence. This mutation is the structural basis for the apo E1 isoform identified upon isoelectric focusing. Five other family members are also carriers of the mutant apo epsilon 1 allele. Two of those were hyperlipidemic and exhibited biochemical characteristics of type III HLP. A second mutation, a deletion of a G in codon 31, is predictive for a reading frameshift that encodes for a premature stop in codon 60. Our inability to identify the product of a second apo E allele in the plasma of the patient and two other members of the KH family corresponds with the heterozygous presence of this mutation in the affected individuals. Both relatives (like the index case) had an increased VLDL cholesterol to plasma TG ratio, which indicates the presence of cholesterol-enriched VLDL particles. We propose that the single base deletion in the apo E gene which is the cause of a non-functional 'null' allele in addition to a probably dominant apo E1 (Gly127-->Asp, Arg158-->Cys) variant of late or incomplete penetrance are the primary genetic defects in this kindred leading to severe dysbetalipoproteinemia.- - - - - - - - - - ranking = 0.73438487883787keywords = family, member (Clic here for more details about this article) |
4/10. Discovery and consequences of apolipoprotein-epsilon(3Groningen): a G-insertion in codon 95/96 that is predicted to cause a premature stop codon.BACKGROUND: We found an unexplained, persistent discrepancy between the outcomes of two apolipoprotein-E (apo-E) genotyping methods for a patient with features of familial dysbetalipoproteinaemia (FD). polymerase chain reaction - restriction fragment length polymorphism resulted in the apo-epsilon(2)/epsilon(2) genotype, whereas minisequencing indicated apo-epsilon(2)/epsilon(3). The discrepancy was predicted to derive from a novel mutation.methods: Sequencing of patient dna, set-up of a mutation analysis method and establishment of mutation occurrence in 19 family members of the proband and investigation of its association with serum lipid indices.RESULTS: Sequencing demonstrated a G-insertion in codon 95 or 96 ((95)AAG-(96-)GAG-->(95)AAG-(96)GGA-G) of the apo-epsilon(3) allele. The mutation, designated apo-epsilon(3Groningen), was predicted to cause a frameshift, a premature stop codon at codon 146 (AAG-->TAA) and the expression of a truncated apo-E protein, if any. Four family members with the apo-epsilon(3Groningen) were identified. Two family members with apo-epsilon(3)/epsilon(3Groningen) had serum lipid indices within reference ranges but low-serum apo-E. Three subjects with apo-epsilon(2)/epsilon(3Groningen), proband included, had serum cholesterol, triglycerides and calculated low-density lipoprotein-cholesterol levels above the reference ranges. Their electrophoresis pattern showed the classical broad-beta band, indicative of FD.CONCLUSION: Apo-epsilon(3Groningen) heterozygosity is unlikely to precipitate FD, unless provoked by compound apo-epsilon(2) heterozygosity or other FD precipitating factors.- - - - - - - - - - ranking = 1.1015773182568keywords = family, member (Clic here for more details about this article) |
5/10. Unmasking of type III hyperlipoproteinemia by hypothyroidism: a dramatic illustration of altered lipoprotein metabolism in a postpartum woman.OBJECTIVE: To illustrate the potential abnormalities in lipoprotein metabolism associated with type III hyper-lipoproteinemia and the modulation of their clinical expression by thyroid hormone and estrogenic status. methods: An illustrative case, with associated clinical and laboratory data, is presented, and relevant clinical and pathophysiologic studies from the literature are reviewed. RESULTS: A 35-year-old woman, at 7 months after delivery of her first child, presented to her family physician with a complaint of painful eruptions on the palms of her hands. On evaluation, she was found to have new hypothyroidism and severe hypertriglyceridemia (>1,569 mg/dL). thyroxine replacement was initiated, and she was referred to the lipid clinic. When seen in the lipid clinic shortly thereafter, her triglyceride level had normalized, but her low-density lipoprotein (LDL) fraction was strikingly elevated (representing a combination of elevated intermediate-density lipoprotein and LDL cholesterol). On physical examination, palmar xanthomas were noted, suggestive of type III hyperlipoproteinemia. This diagnosis was further supported by homozygosity at the apolipoprotein E (apo E) gene locus for the apo E2 allele implicated in this condition. Ultimately, with attainment of euthyroidism in the subsequent weeks, the lipid profile normalized, with the LDL cholesterol concentration particularly reduced at 55 mg/dL. CONCLUSION: Clinical expression of type III hyperlipoproteinemia necessitates interaction between an underlying genetic defect of lipoprotein metabolism (apo E2 homozygosity) and a secondary metabolic insult such as, in the current case, hypothyroidism and possibly breast-feeding-mediated hypoestrogenemia. As such, in patients with type III hyperlipoproteinemia, it is essential to search for exacerbating factors, particularly because the amelioration of such factors may rectify the effects of the underlying dyslipidemia.- - - - - - - - - - ranking = 0.33333333333333keywords = family (Clic here for more details about this article) |
6/10. Tuberous xanthomas associated with olanzapine therapy and hypertriglyceridemia in the setting of a rare apolipoprotein E mutation.OBJECTIVE: To describe a patient with tuberous xanthomas and high levels of cholesterol and triglycerides, who was found to have type III hyperlipoproteinemia (HLP) and a rare apolipoprotein E (apoE) mutation. methods: We present a case report with extensive clinical, laboratory, and genetic documentation. RESULTS: A 33-year-old African American man presented for evaluation of hypertriglyceridemia. His medical history was remarkable for schizophrenia necessitating ongoing olanzapine therapy for the past 6 years. A few months after olanzapine treatment was begun, he noted the development of nontender, firm, papular skin lesions on his elbows and knees. His family history was negative for lipid disorders or premature vascular disease. physical examination revealed the presence of prominent tuberous xanthomas on both elbows and knees. Results of a lipid panel demonstrated a total cholesterol level of 374 mg/dL (9.7 mmol/L) and triglycerides of 828 mg/dL (9.3 mmol/L). A work-up for causes of secondary hyper-triglyceridemia was negative. Results of apoE genotyping by a commercial laboratory showed the E3/E3 genotype, based on gene sequencing at codons 112 and 158. Because the skin lesions were typical for type III HLP, his entire apoE gene was sequenced. This analysis revealed an apoE2/E2 (arginine 145 to cysteine) mutation, previously reported to be a rare cause of type III HLP in 5 patients of African descent. Triglyceride-lowering therapy with gem-fibrozil was initiated, in addition to lifestyle modification. At follow-up several months later, total cholesterol was 276 mg/dL (7.14 mmol/L) and triglycerides were 479 mg/dL (5.41 mmol/L). CONCLUSION: We speculate that olanzapine therapy, with its known metabolic side effects, exacerbated this patient's underlying lipoprotein metabolic abnormality. To our knowledge, this is the first report of an association between olanzapine therapy and tuberous xanthomas and the sixth report of this rare apoE2/E2 (arginine 145 to cysteine) mutation in the literature.- - - - - - - - - - ranking = 0.33333333333333keywords = family (Clic here for more details about this article) |
7/10. Identification and characterization of a new variant of apolipoprotein E (apo E-Kochi).A new variant of apolipoprotein E (apo E), named apo E-Kochi, was identified in the sera of a 29-year-old male with hyperlipoproteinemia as characterized by a broad-beta band. The characteristic double bands of apo E were seen in the isoelectric focusing gel of very low density lipoprotein from the proband and three members of his family. Of the double bands from the probands, the more cationic component was identical to ordinary apo E3 and the other anionic band was located at approximately a distance of one-half charge to the anode side. This anionic band is a new electrophoretical isoform of apo E (apo E-Kochi), and the molecular weight by sodium dodecyl sulfate electrophoresis and its antigenicity against anti apo E serum are the same as apo E3. sequence analysis of lysyl endopeptidase fragments showed that apo E-Kochi differs from normal apo E3 at residue 145, where an arginine residue is substituted for histidine.- - - - - - - - - - ranking = 0.36719243941894keywords = family, member (Clic here for more details about this article) |
8/10. Apolipoprotein E-1Harrisburg: a new variant of apolipoprotein E dominantly associated with type III hyperlipoproteinemia.Apolipoprotein E (apoE) is important in the modulation of the catabolism of chylomicron and very low density lipoprotein (VLDL) remnants. ApoE has three major genetically determined isoproteins in plasma, designated apoE-2, apoE-3 and apoE-4, with homozygosity for the allele coding for apoE-2 being associated with dysbetalipoproteinemia or type III hyperlipoproteinemia (HLP). We describe a new variant of apoE, apoE-1Harrisburg, which is, in contrast to apoE-2, dominantly associated with type III HLP. Five of twelve members of the affected kindred are heterozygous for the mutant form of apoE, and four of the five have type III HLP, while the fifth member has dysbetalipoproteinemia on diet therapy. neuraminidase digestion, which removes charged sialic acid residues, did not alter the electrophoretic position of the apoE-1Harrisburg isoprotein, indicating that the altered charge of apoE-1Harrisburg was not due to sialic acid addition to the apolipoprotein. cysteamine modification, which adds a positively charged group to cysteine, resulted in a shift of apoE-1Harrisburg from the E-1 to the E-2 isoform position, indicating that there is one cysteine in apoE-1Harrisburg as is the case for apoE-3. These results are consistent with apoE-1Harrisburg originating in the allele for apoE-3 with the mutation leading to a negative two-unit charge shift. The definitive identification of a kindred with an apoE variant, apoE-1Harrisburg, dominantly associated with dysbetalipoproteinemia and type III HLP provides a unique opportunity to gain important insights into the structure-function requirements of the E apolipoprotein as well as the mechanisms by which apoE modulates lipoprotein metabolism.- - - - - - - - - - ranking = 0.067718212171208keywords = member (Clic here for more details about this article) |
9/10. Apolipoprotein EBethesda: a new variant of apolipoprotein E associated with type III hyperlipoproteinemia.Apolipoprotein E (apoE) is associated with plasma lipoproteins and is important in modulating the catabolism of remnants of triglyceride-rich lipoproteins. ApoE is a polymorphic protein, and homozygosity for the E2 allele is associated with type III hyperlipoproteinemia. A variant of apoE, apoEBethesda, was found that migrates in the E1 position on isoelectric focusing. Evaluation of the proband and her family showed that both individuals with apoEBethesda had type III hyperlipoproteinemia, and the analysis was consistent with the concept that apoEBethesda was coded by a new E allele and that this allele was expressed in a codominant fashion. The discovery of apoEBethesda and its association with type III hyperlipoproteinemia provides additional evidence for the genetic heterogeneity of the E allele and suggests that a number of different structural mutations of the E apolipoprotein may be associated with the type III phenotype.- - - - - - - - - - ranking = 0.33333333333333keywords = family (Clic here for more details about this article) |
10/10. Unusual xanthomas in a young patient with heterozygous familial hypercholesterolemia and type III hyperlipoproteinemia.We report on a 20-year-old man with the combination of two independent familial lipoprotein disorders: heterozygous familial hypercholesterolemia (FH) and type III hyperlipoproteinemia (HLP). Familial hypercholesterolemia was diagnosed by elevated total and low density lipoprotein cholesterol levels and family history. By denaturing gradient gel electrophoresis, dna sequencing and restriction fragment length polymorphism analysis, a G --> A splice donor mutation in intron 3 of the proband's low density lipoprotein receptor gene was identified as the underlying molecular defect. This mutation was described previously as a receptor-negative founder mutation in norway (FH-Elverum) and subsequently in 6 unrelated heterozygous English patients, creating a severe phenotype of familial hypercholesterolemia. Type III HLP was confirmed by homozygosity for apolipoprotein (apo) E2 and an elevated ratio of very low density lipoprotein cholesterol to serum triglycerides (0.40; normal ratio about 0.20). The patient has unusual flat xanthomas in the interdigital webs of the hands which are normally not found in either disease. These dermatological findings might therefore be indicative of the rare combination of both disorders of lipoprotein metabolism in one individual.- - - - - - - - - - ranking = 0.33333333333333keywords = family (Clic here for more details about this article) |
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