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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
biochemistry, genetics and molecular biology
A missense mutation in the low density lipoprotein receptor gene causes familial hypercholesterolemia in Sephardic Jews
Human Genetics, Volume 91, No. 2, Year 1993
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Description
Familial hypercholesterolemia (FH) is an autosomal dominant disease caused by mutations in the low density lipoprotein (LDL) receptor gene. Here, we characterize an LDL receptor mutation that is associated with a distinct haplotype and that causes FH in the Jewish Sephardic population originating from Safed, a town in northern Israel. The mutation was found in eight FH families originating from this community comprising 10% of heterozygote FH index cases screened in Israel. The mutation was not found in four additional FH heterozygotes whose hypercholesterolemia co-segregated with an identical LDL receptor gene haplotype. A guanine to cytosine substitution results in a missense mutation (asp147 to his) in the fourth repeat of the binding domain encoded by exon 4 of the LDL receptor gene. The mutant receptor protein was synthesized in cultured cells as a 120kDa precursor form that failed to undergo normal processing to a mature cell surface form. Most of the receptor precursors were degraded in the endoplasmic reticulum. The small number of mutant receptors on the cell surface were unable to bind LDL or β very low density lipoprotein. The abnormal behavior of the mutant receptor was reproduced by site-directed mutagenesis and expression of the mutant protein in CHO cells. The mutation can be diagnosed by allele-specific oligonucleotide hybridization of polymerase chain reaction amplified DNA from FH patients. © 1993 Springer-Verlag.
Authors & Co-Authors
Leitersdorf, Eran
Israel, Jerusalem
Hadassah University Medical Centre
Reshef, Ayeleth
Israel, Jerusalem
Hadassah University Medical Centre
Meiner, Vardiella L.
Israel, Jerusalem
Hadassah University Medical Centre
Dann, Eldad J.
Israel, Jerusalem
Hadassah University Medical Centre
Beigel, Yitzhak
Israel, Petah Tiqwa
Rabin Medical Center Israel
van Roggen, Frans Graadt
South Africa, Cape Town
Faculty of Health Sciences
van der Westhuyzen, Deneys R.
South Africa, Cape Town
Faculty of Health Sciences
Coetzee, Gerhard A.
South Africa, Cape Town
Faculty of Health Sciences
Statistics
Citations: 15
Authors: 8
Affiliations: 3
Identifiers
Doi:
10.1007/BF00222714
ISSN:
03406717
e-ISSN:
14321203
Research Areas
Cancer
Genetics And Genomics
Study Design
Cross Sectional Study