Abstract
BackgroundFamilial Hypercholesterolemia is a common autosomal dominantly inherited disease that is most frequently caused by mutations in the gene encoding the receptor for low density lipoproteins (LDLR). Deletions and other major structural rearrangements of the LDLR gene account for approximately 5% of the mutations in many populations.MethodsFive genomic deletions in the LDLR gene were characterized by amplification of mutated alleles and sequencing to identify genomic breakpoints. A diagnostic assay based on duplex PCR for the exon 7 – 8 deletion was developed to discriminate between heterozygotes and normals, and bioinformatic analyses were used to identify interspersed repeats flanking the deletions.ResultsIn one case 15 bp had been inserted at the site of the deleted DNA, and, in all five cases, Alu elements flanked the sites where deletions had occurred. An assay developed to discriminate the wildtype and the deletion allele in a simple duplex PCR detected three FH patients as heterozygotes, and two individuals with normal lipid values were detected as normal homozygotes.ConclusionThe identification of the breakpoints should make it possible to develop specific tests for these mutations, and the data provide further evidence for the role of Alu repeats in intragenic deletions.
Highlights
Familial Hypercholesterolemia is a common autosomal dominantly inherited disease that is most frequently caused by mutations in the gene encoding the receptor for low density lipoproteins (LDLR)
Mutations in the LDLR gene are the most frequent cause of Familial Hypercholesterolemia (FH; Mendelian Inheritance in Man (MIM) #143890), an autosomal dominant condition characterized by elevated concentrations of LDL in blood plasma
We recently showed that Multiplex Ligation-Dependent Probe Amplification (MLPA) [9], which is based on semiquantitative PCR, is a precise and effective diagnostic method [10] that makes it feasible to screen large numbers of patients for mutations of this kind
Summary
Familial Hypercholesterolemia is a common autosomal dominantly inherited disease that is most frequently caused by mutations in the gene encoding the receptor for low density lipoproteins (LDLR). Deletions and other major structural rearrangements of the LDLR gene account for approximately 5% of the mutations in many populations. Mutations in the LDLR gene are the most frequent cause of Familial Hypercholesterolemia (FH; Mendelian Inheritance in Man (MIM) #143890), an autosomal dominant condition characterized by elevated concentrations of LDL in blood plasma. The mutational spectrum is very heterogeneous in the Danish and other populations [2,3], including missense mutations, splice site mutations and large deletions [4]. Major structural rearrangements are usually considered to account for approximately 5% of mutations [5,6].
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