Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0002871 (anemia)
 52,094 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Lecithin:cholesterol acyltransferase (LCAT) deficiency is a genetic disorder associated with low levels of serum HDL cholesterol. The proband of the Finnish LCAT-deficient family had corneal opacities, proteinuria, anemia with stomatocytosis, low serum HDL cholesterol (0.27 mmol/L), and low LCAT activity. Sequence analysis of his LCAT gene revealed compound heterozygosity for two different mutations: a C insertion in exon 1 between nucleotides 932 and 937 and a C-to-T point mutation in exon 6 at position 4976. The C insertion in exon 1 is predicted to result in premature termination and a truncated polypeptide containing only 16 amino acids. The C-to-T point mutation in exon 6 substitutes cysteine for arginine at residue 399. The functional significance of the Arg399-->Cys mutation was examined by expressing the mutated and wild-type LCAT cDNAs in COS cells. COS cells transfected with mutated and wild-type cDNAs showed comparable levels of mature LCAT mRNA. However, LCAT activity in the cell media of COS cells transfected with the mutant LCAT cDNA was significantly lower than that of COS cells transfected with the wild-type cDNA (1.4% versus 12.0% cholesterol esterified, respectively). A polymerase chain reaction-based duplex assay, in which both mutations can be detected simultaneously, was used for preliminary screening of Finnish subjects with serum HDL levels below 0.9 mmol/L; two additional individuals heterozygous for the Arg399-->Cys mutation were identified.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Two different allelic mutations in a Finnish family with lecithin:cholesterol acyltransferase deficiency. 774 57

We investigated the genetic defects in two patients with familial lecithin:cholesterol acyltransferase (LCAT) deficiency. Their clinical manifestations including corneal opacities, anemia, proteinuria, and hypoalphalipoproteinemia were identical for familial LCAT deficiency. Their LCAT activities and the cholesterol esterification rate (CER) were nearly zero, and their LCAT masses were below 10% of normal control values. Sequence analysis of the amplified DNA of case 1 revealed one base deletion of G at base 873 (first position of Val264) in exon 6, leading to a premature termination by frameshift. Sequence analysis of amplified DNA of case 2 revealed a single G to A converting Gly (GGT) to Ser (AGT) substitution at residue 344. When COS-1 cells were transfected with these mutants, LCAT activity in the medium was nearly zero, and the LCAT mass was undetectable (< 0.01 microgram/ml). In contrast, LCAT activity in the medium of COS-1 cells, transfected with wild-type LCAT, was 1.7 nmol/h per ml and the LCAT mass was 0.09 micrograms/ml. The LCAT mass in the cell lysates of the mutants was less than 12% of control for case 1 and 18% of control for case 2. Northern blot analysis of the mRNA of COS-1 cells transfected with the mutants showed the same amounts of LCAT mRNA as compared with wild-type LCAT. Biosynthesis of mutant LCATs was analyzed by pulse-chase and immunocytochemistry in transfected baby hamster kidney cells. SDS-PAGE/fluorography demonstrated that wild-type LCAT was synthesized as a high-mannose type of 56 kDa, which was very slowly converted to a mature form of 67 kDa and was secreted into the media. In contrast to the wild-type LCAT, the mutant precursors were not processed into the mature form but slowly degraded along with chase times. On steady and continuous labeling in the case of wild-type LCAT, the mature 67 kDa form was observed in both the cell lysate and media, whereas no mature form was detected in the cell lysates and media which were transfected mutant LCATs. These data suggest that the mutant LCATs are actually synthesized in an amount comparable to that of wild-type, but they are slowly degraded without being processed into the mature form. The immunocytochemistry revealed that mutant LCATs were mainly retained in the endoplasmic reticulum. These data suggest that these two mutations may disrupt the mutant LCATs' transport from the endoplasmic reticulum into Golgi apparatus, resulting in LCAT deficiency.
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PMID:Two novel point mutations in the lecithin:cholesterol acyltransferase (LCAT) gene resulting in LCAT deficiency: LCAT (G873 deletion) and LCAT (Gly344-->Ser). 865 71

A genetic mendelian autosomal recessive condition of deficiency of lecithin- cholesterol acyltransferase (LCAT) can produce two different diseases: one highly interesting nephrologic picture of complete enzymatic deficiency (lecithin:cholesterol acyltransferase deficiency; OMIM ID #245900; FLD), characterized by the association of dyslipidemia, corneal opacities, anemia and progressive nephropathy; and a partial form (fish eye disease; OMIM ID #136120; FED) with dyslipidemia and progressive corneal opacities only. The diagnosis of FLD falls first of all under the competence of nephrologists, because end-stage renal disease appears to be its most severe outcome. The diagnostic suspicion is based on clinical signs (corneal opacities, more severe anemia than expected for the degree of chronic renal failure, progressive proteinuric nephropathy) combined with histology obtained by kidney biopsy (glomerulopathy evolving toward sclerosis with distinctive lipid deposition). However, the final diagnosis, starting with a finding of extremely low levels of HDL-cholesterol, requires collaboration with lipidology Centers that can perform sophisticated investigations unavailable in common laboratories. To be heterozygous for a mutation of the LCAT gene is one of the monogenic conditions underlying primary hypoalphalipoproteinemia (OMIM ID #604091). This disease, which is characterized by levels of HDL-cholesterol below the 5th percentile of those of the examined population (<28 mg/dL for Italians), has heritability estimates between 40% and 60% and is considered to be a predisposing condition for coronary artery disease. Nevertheless, some monogenic forms, and especially those associated with LCAT deficiency, seem to break the rule, confirming once more the value of a proper diagnosis before drawing prognostic conclusions from a laboratory marker. As in many other rare illnesses, trying to discover all the existing cases will contribute to allow studies broad enough to pave the way for further therapies, in this case also fostering the production by industries of the lacking enzyme by genetic engineering. Epidemiological studies, although done on selected populations such as hypoalphalipoproteinemia patients on dialysis and with the effective genetic tools of today, have been disappointing in elucidating the disease. Spreading the clinical knowledge of the disease and its diagnostic course among nephrologists seems to be the best choice, and this is the aim of our work.
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PMID:[LCAT deficiency: a nephrological diagnosis]. 2180 6