LDLR gene synonymous mutation c.1813C>T results in mRNA splicing variation in a kindred with familial hypercholesterolaemia

Annals of Clinical Biochemistry - Tập 52 Số 6 - Trang 680-684 - 2015
Clement Ho1,2, Fathel Rahman Musa1, Christine Bell3, Simon W. Walker1
1Department of Clinical Biochemistry, Royal Infirmary of Edinburgh, Edinburgh, UK
2Department of Pathology and Laboratory Medicine, KK Women’s and Children’s Hospital, Singapore, Singapore
3Department of Medical Genetics, Aberdeen Royal Infirmary, Aberdeen, UK

Tóm tắt

Familial hypercholesterolaemia, one of the most common inherited diseases in the general population, is associated with mutations in at least three different genes including the low density lipoprotein receptor ( LDLR), apolipoprotein B ( APOB) and protein convertase subtilisin/kexin type 9 ( PCSK9) genes. In this report, we describe an unclassified DNA variant (c.1813C>T; p.Leu605Leu) within exon 12 of the LDLR gene in a kindred in which familial hypercholesterolaemia is associated with c.1813C>T heterozygosity. In silico analysis suggested that c.1813C>T might affect splicing of the LDLR gene by creating a cryptic donor splice site, which was confirmed by RT-PCR coupled with cDNA sequencing, to result in the loss of 34 base pairs in the coding sequence. The latter truncated mRNA is predicted to generate a frameshift leading to a premature stop at codon 652 and early termination of the low density lipoprotein receptor polypeptide chain, and thus provides a molecular basis for the hypercholesterolaemic phenotype. This case report highlights the emerging utility of RNA studies for the molecular diagnosis of familial hypercholesterolaemia in patients with potential mRNA splicing variants.

Từ khóa


Tài liệu tham khảo

10.1111/j.1399-0004.2007.00915.x

10.1161/CIRCRESAHA.115.304660

Goldstein JL, 2001, The metabolic and molecular bases of inherited disease, 8, 2863

10.1146/annurev.ge.24.120190.001025

10.1093/eurheartj/eht273

10.1111/j.1469-1809.2012.00724.x

10.1093/aje/kwh236

10.1002/humu.21348

Do R, Stitziel NO, Won H, et al. Exome sequencing identifies rare LDLR and APOA5 alleles conferring risk for myocardial infarction. Nature 2014; 518: 102–106.

Thông tin
Thông tin xuất bản

Annals of Clinical Biochemistry

Tập 52 Số 6

680-684

Thông tin tác giả