Two different allelic mutations in the lecithin-cholesterol acyltransferase gene associated with the fish eye syndrome. Lecithin-cholesterol acyltransferase (Thr123----Ile) and lecithin-cholesterol acyltransferase (Thr347----Met)

Klein, H.G.; Lohse, P.; Pritchard, P.H.; Bojanovski, D.; Schmidt, H.; Brewer, H.B.

Journal of Clinical Investigation 89(2): 499-506


ISSN/ISBN: 0021-9738
PMID: 1737840
Accession: 041878187

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We have elucidated the genetic defect in a 66-yr-old patient with fish eye syndrome (FES) presenting with severe corneal opacities and hypoalphalipoproteinemia. The patient's plasma concentration of high density lipoprotein (HDL) cholesterol was reduced at 7.7 mg/dl (35.1-65.3 mg/dl in controls) and the HDL cholesteryl ester content was 31% (60-80% in controls); however, total plasma cholesteryl esters were similar to normal (60% of total cholesterol vs. a mean of 66% in controls). The patient's plasma cholesterol esterification rate was slightly reduced at 51 nmol/ml per h (control subjects: 61-106 nmol/ml per h), whereas lecithin-cholesterol acyltransferase (LCAT) activity, assayed using a HDL-like exogenous proteoliposome substrate, was virtually absent (0.9 nmol/ml per h vs. 25.1-27.9 nmol/ml per h in control subjects). DNA sequence analysis of the proband's LCAT gene revealed two separate C to T transitions resulting in the substitution of Thr123 with Ile and Thr347 with Met. The mutation at codon 347 created a new restriction site for the enzyme Nla III. Analysis of the patient's polymerase chain reaction-amplified DNA containing the region of the Thr347 mutation by digestion with Nla III confirmed that the proband is a compound heterozygote for both defects. The patient's daughter, who is asymptomatic despite a 50% reduction of LCAT activity, is heterozygous for the Thr123 .fwdarw. Ile mutation. Our data indicate that the regions adjacent to Thr123 and Thr347 of LCAT may play an important role in HDL cholesterol esterification, suggesting that these regions may contain a portion of the LCAT binding domain(s) for HDL.