Genetic heterogeneity in familial lecithin:cholesterol acyltransferase (LCAT) deficiency.
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Biomedical subjects
Publications and source records attributed to P Teisberg.
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Various common C4 gene products were isolated from serum by immunoprecipitation. After reduction the C4 alpha-, beta-, and gamma-polypeptide chains were studied by two-dimensional electrophoresis. Isoelectrofocusing was performed in the first dimension and sodium dodecyl sulphate polyacrylamide gradient gel electrophoresis in the second. The charge differences behind the electrophoretic C4 polymorphism were shown to reside in the 95,000-u (atomic mass units) alpha-chain. Charge variation closely mirroring the alpha-chain differences were also found in a 49,000-u fragment of the alpha-chain, most probably C4d. The basic beta-chain could not be studied in detail, but no differences were observed with regard to molecular weight or charge of the gamma-chains of the different C4 gene products.
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The tenth Norwegian patient with familial LCAT deficiency is reported. Her family lives in the same area as the three previously reported Norwegian families. The patient is a 26-year-old female with typical findings of the disease--proteinuria and corneal opacities. Total cholesterol was normal, but the main part was present in the free form. Triglycerides were slightly elevated. Kidney function was normal. A large molecular weight fraction of LDL was present in plasma.
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C4-coated Ch(a+) red blood cells (RBC) were used as indicator cells in a serum inhibition reaction of anti-Ch(a), for the determination of the Ch group of serum. This serological study, combined with electrophoretic studies of C4 in a family material, showed that the C4M haplotype product was associated with partial inhibition of anti-Ch(a).
Typing of the sixth component of complement (C6) was performed on serum samples from 167 unrelated Norwegian Lapps. The following allele frequencies were found: C6A, 0.53 and C6B, 0.47. The phenotype distribution was in good agreement with Hardy-Weinberg expectations. Variant phenotypes were not observed. A preliminary material of 1,623 non-Lappish Norwegians showed the following allele frequencies: C6A, 0.59 and C6B, 0.41. The difference in allele distribution between the two materials was statistically significant.
To study possible pathogenetic mechanisms in adult coeliac disease, we performed a metabolic investigation of a component (C3) of the most important effector of humoral immunity, the complement system. Purified and biologically active C3 was labelled with 125I and injected together with 131I-labelled albumin into six patients with adult coeliac disease exhibiting different degrees of disease activity. The same labelled preparations were given to 12 normal individuals. Plasma and urine radioactivity were studied for a total of 8 days. Fractional catabolic rates (FCR) and synthesis rates were calculated by the metabolic clearance method. Other mathematical methods were not used because a final straight exponential was not always obtained, probably owing to extravascular sequestration of protein. An increased FCR was found in most patients, with the highest values seen in active, untreated disease. This suggests that activation of complement by immune complexes may be a pathogenetic factor in adult coeliac disease.
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Linkage relations between the C6 and 33 other genetic marker loci have been analyzed in Norwegian pedigrees, including 114 matings with 388 informative children, by use of the MOSM computer program. No suggestion of linkage was found. Very close or close linkage (theta less than 0.06) has been ruled out for males between C6 and the following 19 marker loci: GPT, HLA + Bf, Rh, C3, Hp, PGM3, Km, Gm, Fy, Gc, ABO Jk, GLO1, K, MNSs, PTC, ACP1, PGM1, and Pi. For several of the relations even loose-linkage is unlikely.
The present study shows that the C4 system as investigated by high voltage agarose gel electrophoresis is highly polymorphic. In a series of unrelated Norwegian adults, where C4 types have been ascertained through segregation in families, six different haplotypes have been found to occur with a frequency exceeding 1%. The genotype frequencies in the population fit expected Hardy-Weinberg distribution. In family material comprising 89 matings with 327 children the distribution of offspring is as expected according to autosomal codominant inheritance of haplotypes.
The results of metabolic studies with radioactively labelled C3 in 14 healthy individuals are presented. Plasma volume determined by labelled C3 was generally higher than when determined by labelled albumin, and different batches of C3 behaved differently during the early part of the experiments. These phenomena are probably caused by C3 inhomogenities which are difficult to detect by usual biochemical and immunological methods. We have, therefore, excluded the first 24 h of the experiments from the mathematical analysis. In this way, rather narrow limits for the metabolic parameters have been obtained.
A study of the family of a patient who had an SLE-like syndrome and an extremely low serum C4 revealed an inheritance of C4 types and HLA region markers which indicated that the patient had 60--70% of "normal" C4 level prior to the onset of disease. Thus the extremely low C4 level during her disease may result from a combination of genetically determined low normal C4 and increased consumption/hyposynthesis secondary to her SLE.
Proteins were separated by prolonged isoelectric focusing in polyacrylamide gels, whereupon C2 bands were detected by a specific hemolytic assay. This was performed by treating the gel with iodine to increase C2 activity, and then developing C2 bands with an agarose gel overlay containing sensitized sheep cells and diluted human serum as a complement source deficient in functional C2. The gene frequencies observed in a material of 122 unrelated adults were: C2(1): 0.97 and C2(2): 0.03. C2 linkage relations and C2 haplotype associations have been examined a family material. It is concluded that C2 is very closely linked to HLA loci.
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