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Mutations in genes encoding subunits of RNA polymerases I and III cause Treacher Collins syndrome

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Abstract

We identified a deletion of a gene encoding a subunit of RNA polymerases I and III, POLR1D, in an individual with Treacher Collins syndrome (TCS). Subsequently, we detected 20 additional heterozygous mutations of POLR1D in 252 individuals with TCS. Furthermore, we discovered mutations in both alleles of POLR1C in three individuals with TCS. These findings identify two additional genes involved in TCS, confirm the genetic heterogeneity of TCS and support the hypothesis that TCS is a ribosomopathy.

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Figure 1: Schematic representation of POLR1D and POLR1C and facial phenotypes of individuals with mutations within POLR1D and POLR1C .

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Acknowledgements

We express our sincere gratitude to the cases, their parents and other family members for their participation in this study, as well as to the clinicians for sending blood samples. We want to thank the Laboratory for Diagnostic Genome Analysis (LDGA) in Leiden and the Forensisch Laboratorium voor DNA Onderzoek (FLDO), as well as the TCS team in Essen and Regensburg for their excellent technical assistance and Ivo Fokkema for his help with constructing the Leiden Open Variation Databases (LOVD). This work was part of the CRANIRARENetwork funded through a grant from the German Ministry of Research and Education to D.R.L. and D.W. (BMBF 01GM0802). The financial support of the National Institutes of Health Research Manchester Biomedical Research Centre and the Healing Foundation to J.D. and M.J.D. is gratefully acknowledged.

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Authors and Affiliations

  1. Center for Human and Clinical Genetics, Leiden University Medical Center (LUMC), Leiden, The Netherlands

    Johannes G Dauwerse, Claudia A L Ruivenkamp, Arie van Haeringen, Dorien J M Peters & Martijn H Breuning

  2. Faculty of Medical and Human Sciences, Manchester Academic Health Sciences Centre, University of Manchester, Manchester, UK

    Jill Dixon, Bronwyn Kerr & Michael J Dixon

  3. Institut für Humangenetik, Universitaetsklinikum Essen, Essen, Germany

    Saskia Seland, Dietmar R Lohmann & Dagmar Wieczorek

  4. Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands

    Lies H Hoefsloot

  5. Department of Pediatrics, Medical Center Haaglanden, The Hague, The Netherlands

    Agnes Clement-de Boers

  6. Praenatal-Medizin München, München, Germany

    Cornelia Daumer-Haas

  7. Medizinisches Versorgungszentrum für Laboratoriumsmedizin, Mikrobiologie und Humangenetik, Mönchengladbach, Germany

    Robert Maiwald

  8. Institute of Human Genetics, Friedrich-Alexander-University of Erlangen-Nuremberg, Erlangen, Germany

    Christiane Zweier

  9. Centre de Référence Neuromusculaire, Hôpital Marin Assistance Publique-Hôpitaux de Paris (AP-HP), Hendaye, France

    Ana M Cobo

  10. Hospital Universitario Central de Asturias, Oviedo, Spain

    Joaquín F Toral

  11. Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, The Netherlands

    A Jeannette M Hoogeboom

  12. Zentrum für Humangenetik am Universitaetsklinikum Regensburg, Regensburg, Germany

    Ute Hehr

  13. Faculty of Life Sciences, University of Manchester, Manchester, UK

    Michael J Dixon

Authors
  1. Johannes G Dauwerse
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  2. Jill Dixon
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  3. Saskia Seland
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  4. Claudia A L Ruivenkamp
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  5. Arie van Haeringen
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  6. Lies H Hoefsloot
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  7. Dorien J M Peters
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  8. Agnes Clement-de Boers
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  9. Cornelia Daumer-Haas
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  10. Robert Maiwald
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  11. Christiane Zweier
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  12. Bronwyn Kerr
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  13. Ana M Cobo
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  14. Joaquín F Toral
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  15. A Jeannette M Hoogeboom
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  16. Dietmar R Lohmann
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  17. Ute Hehr
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  18. Michael J Dixon
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  19. Martijn H Breuning
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  20. Dagmar Wieczorek
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Contributions

Mutation analysis: J.G.D., S.S., D.R.L.

Patient ascertainment including clinical data and/or TCOF1 mutation analysis: J.D., A.v.H., L.H.H., D.J.M.P., A.C.-d.B., C.D.-H., R.M., C.Z., B.K., A.M.C., J.F.T., A.J.M.H., U.H., M.J.D., D.W.

Array analysis: C.A.L.R.

Manuscript writing: J.G.D., M.J.D., D.R.L., M.H.B., D.W.

Study design: J.G.D., A.v.H., D.W.

All authors contributed to the final version of the paper.

Corresponding author

Correspondence to Johannes G Dauwerse.

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Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Methods, Supplementary Tables 1 and 2 and Supplementary Figures 1–4 (PDF 3805 kb)

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Dauwerse, J., Dixon, J., Seland, S. et al. Mutations in genes encoding subunits of RNA polymerases I and III cause Treacher Collins syndrome. Nat Genet 43, 20–22 (2011). https://doi.org/10.1038/ng.724

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  • DOI: https://doi.org/10.1038/ng.724

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