LDLR Database (second edition): new additions to the database and the software, and results of the first molecular analysis

Abstract

Mutations in the LDL receptor gene (LDLR) cause familial hypercholesterolemia (FH), a common autosomal dominant disorder. The LDLR database is a computerized tool that has been developed to provide tools to analyse the numerous mutations that have been identified in the LDLR gene. The second version of the LDLR database contains 140 new entries and the software has been modified to accommodate four new routines. The analysis of the updated data (350 mutations) gives the following informations: (i) 63% of the mutations are missense, and only 20% occur in CpG dinucleotides; (ii) although the mutations are widely distributed throughout the gene, there is an excess of mutations in exons 4 and 9, and a deficit in exons 13 and 15; (iii) the analysis of the distribution of mutations located within the ligand-binding domain shows that 74% of the mutations in this domain affect a conserved amino-acid, and that they are mostly confined in the C-terminal region of the repeats. Conversely, the same analysis in the EGF-like domain shows that 64% of the mutations in this domain affect a non-conserved amino-acid, and, that they are mostly confined in the N-terminal half of the repeats. The database is now accessible on the World Wide Web at http://www.umd.necker.fr

Evaluation of reported pathogenic variants and their frequencies in a Japanese population based on a whole-genome reference panel of 2049 individuals

“…As for another missense variant, p.Arg115His, the allele frequency in 2KJPN was 0.0039, which was greater than expected for causative variants of FH based on the estimated prevalence of 1 in 200-500 in Japan, hence suggesting that these variants are benign or have mild effects. These two variants showed a higher allele frequency in 2KJPN than that of EAs (p < 0.00001), and both of them were originally reported from domestic studies [63,64]. Thus, these variants could be classified as benign evaluated solely from the viewpoint of their relatively high frequencies.…”

Are common disease susceptibility alleles the same in outbred and founder populations?

“…More than 770 mutations have been discovered in the LDL receptor to date. 33,34 Mutations in LDLR have been associated with familial hypercholesterolemia, a disorder characterized by high levels of LDL, and variation in the gene also contributes significantly to LDL levels in the general population. 35 -37 The NcoI site is a polymorphism in exon 18, where the ' þ ' allele is on a haplotype that is associated with increased total and LDL-cholesterol, 38,39 consistent with our finding of an association with 'high LDL' in the Hutterites.…”

Efficacy and Safety of Ezetimibe Coadministered With Atorvastatin or Simvastatin in Patients With Homozygous Familial Hypercholesterolemia

“…31,32 Individual reported base pair changes or deletions in the LDL receptor gene were compared against published DNA sequences, allele designations, and mutational classes of the LDL receptor gene. 9,[33][34][35] …”