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(Arteriosclerosis, Thrombosis, and Vascular Biology. 1996;16:294-303.)
© 1996 American Heart Association, Inc.

Articles

Two Novel Molecular Defects in the LCAT Gene Are Associated With Fish Eye Disease

Jan Albert Kuivenhoven; Anton F.H. Stalenhoef; John S. Hill; Pierre N.M. Demacker; A. Errami; John J.P. Kastelein; P. Haydn Pritchard

From the Department of Hemostasis, Thrombosis, Atherosclerosis and Inflammation Research, Academic Medical Center, University of Amsterdam, the Netherlands (J.A.K., A.E., J.J.P.K.); Department of Medicine, Division of General Internal Medicine, University Hospital Nijmegen, the Netherlands (A.F.H.S.); and the Atherosclerosis Specialty Laboratory, Department of Pathology and Laboratory Medicine, St Paul's Hospital and University of British Columbia, Vancouver Canada (J.S.H., P.H.P.).

Correspondence to P. Haydn Pritchard, PhD, Healthy Heart Program, St Paul's Hospital, 1081 Burrard St, Vancouver, British Columbia, Canada V6Z 1Y6. E-mail hpcy@unixg.ubc.ca.

Abstract A 53-year-old man with a severely reduced HDL cholesterol level, dense corneal opacities, normal renal function, and premature coronary artery disease was investigated together with 16 members of his family. The proband was diagnosed with fish eye disease. As in previously reported patients with fish eye disease, the endogenous plasma cholesterol esterification rate was near normal, yet lecithin:cholesterol acyltransferase (LCAT) activity was almost absent when measured with exogenous HDL analogues used as substrate. Direct sequencing of the LCAT gene revealed two novel missense mutations in exon 1 and exon 4, resulting in the substitution of Pro¹⁰ with Gln (P10Q) and Arg¹³⁵ with Gln (R135Q), respectively. Both missense mutations were located on different alleles. Genetic analysis by polymerase chain reaction revealed 4 carriers of the P10Q and 3 carriers of the R135Q defect. Functional assessment of both missense mutations revealed that when exogenous HDL analogues were used as substrate, the specific activity of rLCAT_P10Q was 18% of wild type (WT); however, when LDL was used as substrate, the activity was 146% of WT. By contrast, rLCAT_R135Q was inactive against both substrates. Thus, we conclude that the LCAT_R135D mutation is causative for complete LCAT deficiency and that the clinical phenotype of fish eye disease seen in this patient is due to the Pro¹⁰ mutation. The presence of premature coronary artery disease in the absence of other risk factors in this new case of fish eye disease raises questions regarding the risk of atherosclerosis, which has previously been reported to be nonexistent.

Key Words: HDL deficiency • lecithin:cholesterol acyltransferase • fish eye disease • corneal opacities

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