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Gene expression studies in cells from primary ciliary dyskinesia patients identify 208 potential ciliary genes

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Abstract

Cilia are small cellular projections that either act as sensors (primary cilia) or propel fluid over the epithelia of various organs (motile cilia). The organellum has gained much attention lately because of its involvement in a group of human diseases called ciliopathies. Primary ciliary dyskinesia (PCD) is an autosomal recessive ciliopathy caused by mutations in cilia motility genes. The disease is characterized by recurrent respiratory tract infections due to the lack of an efficient mucociliary clearance. We performed whole-genome gene expression profiling in bronchial biopsies from PCD patients. We used the quality threshold clustering algorithm to identify groups of genes that revealed highly correlated RNA expression patterns in the biopsies. The largest cluster contained 372 genes and was significantly enriched for genes related to cilia. The database and literature search showed that 164 genes in this cluster were known cilia genes, strongly indicating that the remaining 208 genes were likely to be new cilia genes. The tissue expression pattern of the 208 new cilia genes and the 164 known genes was consistent with the presence of motile cilia in a given tissue. The analysis of the upstream promotor sequences revealed evidence for RFX transcription factors binding site motif in both subgroups. Based on the correlated expression patterns in PCD-affected tissues, we identified 208 genes that we predict to be involved in cilia biology. Our predictions are based directly on the human material and not on model organisms. This list of genes provides candidate genes for PCD and other ciliopathies.

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Acknowledgments

The cooperation of all the Polish families who participated in this study was invaluable. We thank Jackie Senior for editing the manuscript, Ewa Rutkiewicz for laboratory assistance, and the staff of the Genomics Facility, UMCG, for scientific and technical work. MG was supported by the International PhD Program of Utrecht University, The Netherlands coordinated by the International Institute of Molecular and Cell Biology, Warsaw, Poland.

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Authors and Affiliations

  1. International Institute of Molecular and Cell Biology, Warsaw, Poland

    Maciej Geremek & Michał Witt

  2. Department of Genetics, University Medical Center Groningen, 9700 RB, Groningen, The Netherlands

    Maciej Geremek, Marcel Bruinenberg & Cisca Wijmenga

  3. Complex Genetics Group, Department of Biomedical Genetics, University Medical Center Utrecht, 3508 AB, Utrecht, The Netherlands

    Maciej Geremek & Cisca Wijmenga

  4. Department of Molecular and Clinical Genetics, Institute of Human Genetics, Poznan, Poland

    Ewa Ziętkiewicz & Michał Witt

  5. Institute of Tuberculosis and Lung Diseases, Rabka, Poland

    Andrzej Pogorzelski

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  1. Maciej Geremek
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  2. Marcel Bruinenberg
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  3. Ewa Ziętkiewicz
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  4. Andrzej Pogorzelski
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  5. Michał Witt
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Correspondence to Maciej Geremek.

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M. Witt and C. Wijmenga equally contributed to the manuscript.

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Supplementary information

Supplementary table 1. Electron microscopy, nitric oxide measurements and situs status in the patients.

Supplementary table 2. Known ciliary genes in the cluster A

Supplementary table 3. Cluster A genes previously not linked to cilia

Supplementary table 4. Transcription factors significantly over-represented in the 500 bp upstream sequences of analyzed groups of genes

Supplementary material 1 (DOC 12 kb)

Supplementary material 2 (DOC 297 kb)

Supplementary material 3 (DOC 370 kb)

Supplementary material 4 (DOC 137 kb)

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Geremek, M., Bruinenberg, M., Ziętkiewicz, E. et al. Gene expression studies in cells from primary ciliary dyskinesia patients identify 208 potential ciliary genes. Hum Genet 129, 283–293 (2011). https://doi.org/10.1007/s00439-010-0922-4

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