Low-density lipoprotein receptor gene (LDLR) world-wide website in familial hypercholesterolaemia: update, new features and mutation analysis
Introduction
Familial hypercholesterolaemia (FH) is an autosomal dominant disorder with estimated frequencies of 1 in 500 and 1 in a million in most populations for heterozygotes and homozygotes respectively [1]. Mutations in the low-density lipoprotein receptor gene (LDLR) give rise to familial hypercholesterolaemia (FH). The gene is located on chromosome 19p13.1–13.3 [2], spans 45 kb and comprises of 18 exons and 17 introns that encode a mature protein of 839 amino acids [3]. The LDL-receptor is made up of six functional domains; the signal sequence, ligand binding domain, epidermal growth factor (EGF) precursor-like domain, O-linked sugar domain, transmembrane domain and the cytoplasmic domain [3]. In 1997, a FH website for LDLR mutations was established (http://www.ucl.ac.uk/fh) [4]. Originally, the database consisted of two core elements; a gene map and a mutation list. This report describes the updates, new features and evaluates the mutations found to date.
Section snippets
Familial hypercholesterolaemia website new and updated features
On accessing the database, the user is immediately taken to an introductory screen giving hypertext-linked access to other areas of the database, mutation database (table and gene map), major rearrangement database, polymorphism databases (description and incidence), haplotype databases, table of double mutants, table of founder gene effect mutations, tables of published LDLR oligonucleotides, and useful links and references.
The mutation database continues to exist in two formats, the gene map,
Analysis of mutations
To date 683 unique mutations are found on the FH website, 592 (86.7%) involved 1–24 bp whilst 92 (13.5%) were major rearrangements >25 bp in size. A total of 45 (6.6%) splice site mutations have been reported, 144 (21.1%) minor rearrangements and 402 (58.9%) missense mutations. Only 46 of the 402 missense mutations occurred at CpG sites resulting in a frequency of 11.4%, similar to that reported in the study of 157 FH homozygotes and 13 heterozygotes, 15% [1]. The spectrum of mutations
Conclusion
New mutations can still be submitted to the FH website electronically, but now mutations not seen previously in a particular ethnic group and haplotype data can also be submitted. The information submitted is held until it can be reviewed appropriately and then the new mutations are added to the database. The inclusion of an e-mail address is essential for any queries and acceptance of the mutation, after review, to the database.
We believe that the database will continue to be of use to those
Acknowledgements
Thanks to all who have contributed to this database, especially to Professor Stefano Bertolini who verified many of the mutation entries. This work is supported in part by Merck Sharp Dohme, the John Pinto Foundation, the British Heart Foundation (Grants RG95007 and RG93008) and MEDPED, University of Utah, Salt Lake City, Utah.
References (14)
- et al.
A World Wide Web site for low-density lipoprotein receptor gene mutations in familial hypercholesterolaemia: sequence based, tabular and direct submission data handling
Am. J. Cardiol.
(1998) - et al.
Mutations in the low density lipoprotein receptor gene of familial hypercholesterolaemic patients detected by denaturing gradient gel electrophoresis and direct sequencing
J. Lipid Res.
(1995) - et al.
The human LDL receptor: a cysteine-rich protein with multiple Alu sequences in its mRNA
Cell
(1984) - et al.
Molecular genetics of the LDL receptor gene in familial hypercholesterolaemia
Hum. Mutat.
(1992) - et al.
Assignment of the human gene for the low density lipoprotein receptor to chromosome 19: synteny of a receptor, a ligand, and a genetic disease
Proc. Natl. Acad. Sci.
(1984) - et al.
The LDL receptor gene: a mosaic of exons shared with different proteins
Science
(1985) - et al.
Screening for mutations in exon 4 of the LDL receptor gene in a German population with severe hypercholesterolaemia
Hum. Genet.
(1995)