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Home arrow Research arrow Research Lines arrow Cystic fibrosis: the study of novel gene variants and gene variants in novel genes
Cystic fibrosis: the study of novel gene variants and gene variants in novel genes Print E-mail


Functional interaction between CFTR (altered in cystic fibrosis) and SLC26A3 (altered in chloridorrhea)
Functional interaction between CFTR (altered in cystic fibrosis) and SLC26A3 (altered in chloridorrhea)


Superimposition of protein models of human beta defensin 1 (blue) and 3 (red)
Superimposition of protein models of human beta defensin 1 (blue) and 3 (red)


The conserved sequence tags (CSTs) database includes a large number of not previously described exons and/or elements that could play a role in regulating CFTR expression. Gene variants in noncoding regions of CFTR may be functionally related to altered activity of the protein and thus may act as disease-causing mutations or modifiers of the CF phenotype. The CST database is a collection of conserved sequence elements, identified by a systematic genomic sequence comparison between a set of human genes involved in the pathogenesis of genetic disorders and their murine counterparts. Human and mouse genomic sequences were compared by BLAST specifically designed for aligning two long genomic sequences. CSTs are extensively annotated with respect to exon/intron structure and other biological parameters. The CST database contains data about 1022 genes. About 60,000 human/mouse conserved tags are known covering about 8% of genomic sequences. We selected a group of about 50 CSTs within CFTR intron regions that have a level of phylogenetic homology between human and mouse of >70%. Then in collaboration with the group of bioinformatics of G. Paolella we started to analyze these sequences in two groups of CF patients. Firstly, CF patients bearing one or both undetected CFTR mutations after scanning the whole coding regions of the CFTR gene. This study will reveal if CST variants act as disease-causing mutations. Secondly, we will examine several groups of CF patients that have different clinical expressions of the disease (i.e., a severe versus mild pulmonary phenotype; pancreatic sufficiency versus pancreatic insufficiency; presence or absence of severe liver expression; atypical monosymptomatic forms of CF) to verify if gene variants within CST regions can act as modifiers of the CF phenotype. The SLC26 gene family encodes a group of proteins that act as ionic channels and are expressed in various types of human tissues. Several of these proteins are also related to human diseases. For instance, SLC26A3 causes chloride diarrhea (CLD), a rare and severe chronic diarrhea with a loss of chloride. We studied 12 CLD children and identified a series of novel causative mutations. We also evaluated a new therapy which reverted chronic diarrhea in one of these patients (Berni Canani et al. 2004). More recently, it was demonstrated that some SLC26 channels interact with the CFTR protein causing a six-fold increase of the conductance activity of both proteins (Gray 2004)1. This prompted us to investigate the interaction between the CLD and CFTR systems. To this aim we selected a group of CF patients bearing one or both undetected mutations after scanning the coding regions of the CFTR gene. We are now scanning the whole coding regions of the SLC26 genes. This study will reveal if gene variants within SLC26 genes act as disease-causing mutations for CF. We also looked for SLC26 gene variants in CF patients affected by different clinical expressions of the disease (i.e., severe versus mild pulmonary phenotype; pancreatic sufficiency versus pancreatic insufficiency; presence or absence of severe liver expression; atypical monosymptomatic forms of CF). The aim of this part of our study is to determine whether these gene variants modify the CF phenotype. Lastly, we will express in vitro several mutations of the SLC26A3 and CFTR genes, to determine whether or not these variants affect the interaction between the proteins. For the latter study we will carry out electrophysiological experiments.

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