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Title: Polyvariant mutant cystic fibrosis transmembrane conductance regulator genes. The polymorphic (Tg)m locus explains the partial penetrance of the T5 polymorphism as a disease mutation
Authors: Cuppens, Harry ×
Lin, Wei
Jaspers, Martine
Costes, B
Teng, Hui
Vankeerberghen, An
Jorissen, Mark
Droogmans, Guillaume
Reynaert, Ingrid
Goossens, M
Nilius, Bernd
Cassiman, Jean-Jacques #
Issue Date: Jan-1998
Publisher: Rockefeller univ press
Series Title: Journal of Clinical Investigation vol:101 issue:2 pages:487-96
Abstract: In congenital bilateral absence of the vas deferens patients, the T5 allele at the polymorphic Tn locus in the CFTR (cystic fibrosis transmembrane conductance regulator) gene is a frequent disease mutation with incomplete penetrance. This T5 allele will result in a high proportion of CFTR transcripts that lack exon 9, whose translation products will not contribute to apical chloride channel activity. Besides the polymorphic Tn locus, more than 120 polymorphisms have been described in the CFTR gene. We hypothesized that the combination of particular alleles at several polymorphic loci might result in less functional or even insufficient CFTR protein. Analysis of three polymorphic loci with frequent alleles in the general population showed that, in addition to the known effect of the Tn locus, the quantity and quality of CFTR transcripts and/or proteins was affected by two other polymorphic loci: (TG)m and M470V. On a T7 background, the (TG)11 allele gave a 2.8-fold increase in the proportion of CFTR transcripts that lacked exon 9, and (TG)12 gave a sixfold increase, compared with the (TG)10 allele. T5 CFTR genes derived from patients were found to carry a high number of TG repeats, while T5 CFTR genes derived from healthy CF fathers harbored a low number of TG repeats. Moreover, it was found that M470 CFTR proteins matured more slowly, and that they had a 1.7-fold increased intrinsic chloride channel activity compared with V470 CFTR proteins, suggesting that the M470V locus might also play a role in the partial penetrance of T5 as a disease mutation. Such polyvariant mutant genes could explain why apparently normal CFTR genes cause disease. Moreover, they might be responsible for variation in the phenotypic expression of CFTR mutations, and be of relevance in other genetic diseases.
URI: 
ISSN: 0021-9738
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Department of Human Genetics - miscellaneous
Laboratory of Ion Channel Research
Hepatology
Research Group Experimental Oto-rhino-laryngology
Human Mutations and Polymorphisms Section (-)
Physiology Section (-)
Department of Cellular and Molecular Medicine - miscellaneous
Forensic Biomedical Sciences
× corresponding author
# (joint) last author

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