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Clinically applicable mutation screening in familial hypercholesterolemia
Author(s) -
Nissen Henrik,
Guldberg Per,
Hansen Annebirthe Bo,
Petersen Niels Erik,
Hørder Mogens
Publication year - 1996
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/(sici)1098-1004(1996)8:2<168::aid-humu9>3.0.co;2-7
Subject(s) - familial hypercholesterolemia , biology , mutation , genetics , exon , apolipoprotein b , ldl receptor , phenotype , splice , gene , splice site mutation , microbiology and biotechnology , alternative splicing , lipoprotein , cholesterol , endocrinology
Mutations in the LDL receptor ( LDLR ) gene and the codon 3500 region of the apolipoprotein (apo) B‐100 gene result in the clinically indistinguishable phenotypes designated familial hypercholesterolemia (FH) and familial defective apo B‐100 (FDB), respectively. Introduction of genetic diagnosis in phenotypic FH families may remove the diagnostic inaccuracies known from traditional clinical/biochemical FH diagnosis and allow more differentiated prognostic evaluations and genetic counseling of FH/FDB families. Previous genetic screening methods for FH have, however, been too cumbersome for routine use, however. To overcome these problems, we designed a mutation screening assay based on the highly sensitive denaturing gradient gel electrophoresis (DGGE) technique. The setup allows within 24 hr to pinpoint if and where a potential mutation is located in the LDLR promoter, the 18 LDLR gene exons and corresponding intronic splice site sequences, or in the codon 3500 region of apo B‐100. The pinpointed region is subsequently sequenced. As an evaluation of the sensitivity, we demonstrated the ability of the assay to detect 27 different mutations or polymorphisms covering all the examined regions, except LDLR exon 16. In conclusion, a simple, but sensitive, clinically applicable mutation screening assay based on the DGGE principle may reveal the underlying mutation in most FH/FDB families and offer a tool for a more differentiated prognostic and therapeutic evaluation in FH/FDB. © 1996 Wiley‐Liss, Inc.