HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: D400030-JLR200v1 46/2/366    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Wang, J. Articles by Hegele, R. A. Search for Related Content PubMed PubMed Citation Articles by Wang, J. Articles by Hegele, R. A. Social Bookmarking                      What's this?

Journal of Lipid Research, Vol. 46, 366-372, February 2005
Copyright © 2005 by American Society for Biochemistry and Molecular Biology

Methods

Multiplex ligation-dependent probe amplification of LDLR enhances molecular diagnosis of familial hypercholesterolemia

Jian Wang, Matthew R. Ban and Robert A. Hegele¹

Robarts Research Institute, London, Ontario, Canada N6A 5K8

¹ To whom correspondence should be addressed. e-mail: hegele{at}robarts.ca

Autosomal dominant (AD) familial hypercholesterolemia [FH; Mendelian Inheritance in Man (MIM) 143890] typically results from mutations in the LDL receptor gene (LDLR), which are now commonly diagnosed using exon-by-exon screening methods, such as exon-by-exon sequence analysis (EBESA) of genomic DNA (gDNA). However, many patients with FH have no LDLR mutation identified by this method. Part of the diagnostic gap is attributable to the genetic heterogeneity of AD FH, but another possible explanation is inadequate sensitivity of EBESA to detect certain mutation types, such as large deletions or insertions in LDLR. Multiplex ligation-dependent probe amplification (MLPA) is a new method that detects larger gDNA alterations that are overlooked by EBESA. We hypothesized that some FH patients with no LDLR mutation detectable by EBESA would have an abnormal LDLR MLPA pattern. In 70 unrelated FH patients, 44 had LDLR mutations detected by EBESA, including missense, RNA splicing, nonsense, or small deletion mutations, and 5 had the APOB R3500Q mutation. Among the remaining 21 AD FH patients with no apparent LDLR mutation, we found abnormal LDLR MLPA patterns in 12 and then demonstrated the deleted sequence in 5 of these.

These findings indicate that MLPA may be a useful new adjunctive tool for the molecular diagnosis of FH.

Supplementary key words atherosclerosis • genetics • monogenic disorders • DNA analysis • low density lipoprotein receptor gene

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				Z. Awan, K. Alrasadi, G.A. Francis, R.A. Hegele, R. McPherson, J. Frohlich, D. Valenti, B. de Varennes, M. Marcil, C. Gagne, et al. Vascular Calcifications in Homozygote Familial Hypercholesterolemia Arterioscler. Thromb. Vasc. Biol., April 1, 2008; 28(4): 777 - 785. [Abstract] [Full Text] [PDF]

				R. L. Pollex and R. A. Hegele Copy Number Variation in the Human Genome and Its Implications for Cardiovascular Disease Circulation, June 19, 2007; 115(24): 3130 - 3138. [Full Text] [PDF]

				R. A. Hegele Copy-number variations add a new layer of complexity in the human genome Can. Med. Assoc. J., February 13, 2007; 176(4): 441 - 442. [Full Text] [PDF]

				O. W. Souverein, J. C. Defesche, A. H. Zwinderman, J. J.P. Kastelein, and M. W.T. Tanck Influence of LDL-receptor mutation type on age at first cardiovascular event in patients with familial hypercholesterolaemia Eur. Heart J., February 1, 2007; 28(3): 299 - 304. [Abstract] [Full Text] [PDF]

				L. S. Sullivan, S. J. Bowne, C. R. Seaman, S. H. Blanton, R. A. Lewis, J. R. Heckenlively, D. G. Birch, D. Hughbanks-Wheaton, and S. P. Daiger Genomic Rearrangements of the PRPF31 Gene Account for 2.5% of Autosomal Dominant Retinitis Pigmentosa. Invest. Ophthalmol. Vis. Sci., October 1, 2006; 47(10): 4579 - 4588. [Abstract] [Full Text] [PDF]