Genomic rearrangements in the CFTR gene: extensive allelic heterogeneity and diverse mutational mechanisms

Audrezet, M. P., Chen, J. M., Raquenes, O., Chuzhanova, N., Giteau, K., Le Marechal, C., Quere, I., Cooper, David Neil ORCID: https://orcid.org/0000-0002-8943-8484 and Ferec, C. 2004. Genomic rearrangements in the CFTR gene: extensive allelic heterogeneity and diverse mutational mechanisms. Human Mutation 23 (4) , pp. 343-357. 10.1002/humu.20009

Full text not available from this repository.

Abstract

Cystic fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance regulator gene (CFTR/ABCC7). Despite the extensive and enduring efforts of many CF researchers over the past 14 years, up to 30% of disease alleles still remain to be identified in some populations. It has long been suggested that gross genomic rearrangements could account for these unidentified alleles. To date, however, only a few large deletions have been found in the CFTR gene and only three have been fully characterized. Here, we report the first systematic screening of the 27 exons of the CFTR gene for large genomic rearrangements, by means of the quantitative multiplex PCR of short fluorescent fragments (QMPSF). A well-characterized cohort of 39 classical CF patients carrying at least one unidentified allele (after extensive and complete screening of the CFTR gene by both denaturing gradient gel electrophoresis and denaturing high-performance liquid chromatography) participated in this study. Using QMPSF, some 16% of the previously unidentified CF mutant alleles were identified and characterized, including five novel mutations (one large deletion and four indels). The breakpoints of these five mutations were precisely determined, enabling us to explore the underlying mechanisms of mutagenesis. Although non-homologous recombination may be invoked to explain all five complex lesions, each mutation appears to have arisen through a different mechanism. One of the indels was highly unusual in that it involved the insertion of a short 41 bp sequence with partial homology to a retrotranspositionally-competent LINE-1 element. The insertion of this ultra-short LINE-1 element (dubbed a "hyphen element") may constitute a novel type of mutation associated with human genetic disease.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Subjects:	R Medicine > R Medicine (General) R Medicine > RZ Other systems of medicine
Uncontrolled Keywords:	Substances CFTR protein, human Cystic Fibrosis Transmembrane Conductance Regulator Secondary Source ID OMIM/219700 OMIM/602421
Publisher:	Wiley-Blackwell
ISSN:	1059-7794
Last Modified:	25 Oct 2022 10:02
URI:	https://orca.cardiff.ac.uk/id/eprint/60925

Citation Data

Cited 105 times in Scopus. View in Scopus. Powered By Scopus® Data

Actions (repository staff only)

Edit Item