Quick Search:

uzh logo
Browse by:
bullet
bullet
bullet
bullet

Zurich Open Repository and Archive 

Mátyás, G; Alonso, S; Patrignani, A; Marti, M; Arnold, E; Magyar, I; Henggeler, C; Carrel, T; Steinmann, B; Berger, W (2007). Large genomic fibrillin-1 (FBN1) gene deletions provide evidence for true haploinsufficiency in Marfan syndrome. Human Genetics, 122(1):23-32.

Full text not available from this repository.

Abstract

Mutations in the FBN1 gene are the major cause of Marfan syndrome (MFS), an autosomal dominant connective tissue disorder, which displays variable manifestations in the cardiovascular, ocular, and skeletal systems. Current molecular genetic testing of FBN1 may miss mutations in the promoter region or in other noncoding sequences as well as partial or complete gene deletions and duplications. In this study, we tested for copy number variations by successively applying multiplex ligation-dependent probe amplification (MLPA) and the Affymetrix Human Mapping 500 K Array Set, which contains probes for approximately 500,000 single-nucleotide polymorphisms (SNPs) across the genome. By analyzing genomic DNA of 101 unrelated individuals with MFS or related phenotypes in whom standard genetic testing detected no mutation, we identified FBN1 deletions in two patients with MFS. Our high-resolution approach narrowed down the deletion breakpoints. Subsequent sequencing of the junctional fragments revealed the deletion sizes of 26,887 and 302,580 bp, respectively. Surprisingly, both deletions affect the putative regulatory and promoter region of the FBN1 gene, strongly indicating that they abolish transcription of the deleted allele. This expectation of complete loss of function of one allele, i.e. true haploinsufficiency, was confirmed by transcript analyses. Our findings not only emphasize the importance of screening for large genomic rearrangements in comprehensive genetic testing of FBN1 but, importantly, also extend the molecular etiology of MFS by providing hitherto unreported evidence that true haploinsufficiency is sufficient to cause MFS.

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Functional Genomics Center Zurich
04 Faculty of Medicine > Institute of Medical Molecular Genetics
08 University Research Priority Programs > Systems Biology / Functional Genomics
DDC:570 Life sciences; biology
610 Medicine & health
Language:English
Date:August 2007
Deposited On:28 Dec 2009 07:13
Last Modified:27 Nov 2013 21:01
Publisher:Springer
ISSN:0340-6717
Additional Information:The original publication is available at www.springerlink.com
Publisher DOI:10.1007/s00439-007-0371-x
PubMed ID:17492313
Citations:Web of Science®. Times Cited: 31
Google Scholar™

Users (please log in): suggest update or correction for this item

Repository Staff Only: item control page