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The Journal of Lipid Research, Vol. 40, 213-220, February 1999
Copyright © 1999 by Lipid Research, Inc.

Original Article

Phenotypic consequences of a deletion of exons 2 and 3 of the LDL receptor gene

Olaug K. Rødningena,b, Serena Tonstadc, Jheem D. Medhd, David A. Chappelld, Leiv Osee, and Trond P. Lerenb
a Department of Medical Genetics, Ullevål University Hospital, N-0407 Oslo, Norway
b Medinnova/MSD Cardiovascular Research Centre, Rikshospitalet, N-0027 Oslo, Norway
c Department of Preventive Cardiology, Ullevål University Hospital, N-0407 Oslo, Norway
d University of Iowa College of Medicine, Iowa City, IA 52242,
e Lipid Clinic, Rikshospitalet, N-0027 Oslo, Norway

Correspondence to: Olaug K. Rødningen

Screening for structural alterations of the low density lipoprotein (LDL) receptor gene by Southern blot analysis revealed an abnormal band pattern in one subject with a clinical diagnosis of homozygous familial hypercholesterolemia (FH). The molecular defect was further characterized by polymerase chain reaction and cDNA sequencing. These analyses identified a 4.8 kb in-frame deletion of exons 2 and 3, where exon 1 was spliced to exon 4. This deletion is expected to produce a receptor that has lost the two first cysteine-rich repeats of the ligand-binding domain. Previously published data of in vitro site-directed mutagenesis has shown that binding of LDL to such a receptor is reduced to 70% of normal. A mild phenotype in our FH homozygote is consistent with that observation. In contrast, heterozygotes carrying this deletion have a relatively more severe phenotype that is comparable to that of heterozygotes carrying a null-allele. A severe phenotype was also found in a compound heterozygote carrying this deletion. Possible mechanisms for this phenotypic variability are discussed.—Rødningen, O. K., S. Tonstad, J. D. Medh, D. A. Chappell, L. Ose, and T. P. Leren. Phenotypic consequences of a deletion of exons 2 and 3 of the LDL receptor gene. J. Lipid Res. 1999. 40: 213–220.

Supplementary key words: deletion, familial hypercholesterolemia, homozygous FH, low density lipoprotein receptor


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