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The CLCA gene locus as a modulator of the gastrointestinal basic defect in cystic fibrosis

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Abstract

To determine whether the CLCA gene family of calcium-activated chloride channels is a modulator of the basic defect of cystic fibrosis (CF), an association study was performed with polymorphic microsatellite markers covering a 40-Mbp region spanning the CLCA gene locus on human chromosome 1p in CF patients displaying CF transmembrane conductance regulator (CFTR)-independent residual chloride conductance in gastrointestinal epithelia. Statistically significant association of the electrophysiological phenotype with the allele distribution of markers 5’ of and within the CLCA locus was observed. Transmission disequilibrium and the significance of the association decreased within the locus from hCLCA2 towards hCLCA4. Expression of hCLCA1 and hCLCA4 in human rectal mucosa was proven by microarray analysis. The CLCA gene region was identified to encode mediators of DIDS-sensitive anion conductance in the human gastrointestinal tract that modulate the CF basic defect.

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Acknowledgements

We thank Ulrike Laabs and Radha Soedhof for excellent technical assistance, and Drs. Inez Bronsveld and Andrea van Barneveld for helpful discussions. Financial support by the Deutsche Forschungsgemeinschaft to A.D.G. and B.T. (SFB 621) and the European Union to B.T. (QL G1-CF-2001-01005) is gratefully acknowledged.

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Authors and Affiliations

  1. Department of Pediatrics and Clinical CF Research Group, Medical School Hannover, Carl-Neuberg Str. 1, 30625, Hannover, Germany

    Margit Ritzka, Frauke Stanke, Silke Jansen & Burkhard Tümmler

  2. Department of Pathology, School of Veterinary Medicine Hannover, Bünteweg 17, 30559, Hannover, Germany

    Achim D. Gruber

  3. AG Molecular Biology, Clinic for Internal Medicine II und Clinic for Neurosurgery, Clinic of the Friedrich-Schiller-University Jena, Erlangerallee 101, 07747, Jena, Germany

    Larissa Pusch & Stefan Woelfl

  4. Ijsselland Hospital, P.O. Box 690, 2900, AR Capelle a/d Ijssel, The Netherlands

    Henk J. Veeze

  5. Department of Clinical Genetics, Erasmus MC, Dr. Molewaterplein 50, 3015, GE Rotterdam, The Netherlands

    Dicky J. Halley

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  1. Margit Ritzka
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  2. Frauke Stanke
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Correspondence to Burkhard Tümmler.

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Ritzka, M., Stanke, F., Jansen, S. et al. The CLCA gene locus as a modulator of the gastrointestinal basic defect in cystic fibrosis. Hum Genet 115, 483–491 (2004). https://doi.org/10.1007/s00439-004-1190-y

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