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Partial deficiency of the C-terminal-domain phosphatase of RNA polymerase II is associated with congenital cataracts facial dysmorphism neuropathy syndrome

Nature Genetics volume 35, pages 185–189 (2003)Cite this article

Abstract

Congenital cataracts facial dysmorphism neuropathy (CCFDN) syndrome (OMIM 604168) is an autosomal recessive developmental disorder that occurs in an endogamous group of Vlax Roma (Gypsies; refs. 1–3). We previously localized the gene associated with CCFDN to 18qter, where a conserved haplotype suggested a single founder mutation4. In this study, we used recombination mapping to refine the gene position to a 155-kb critical interval. During haplotype analysis, we found that the non-transmitted chromosomes of some unaffected parents carried the conserved haplotype associated with the disease. Assuming such parents to be completely homozygous across the critical interval except with respect to the disease-causing mutation, we developed a new 'not quite identical by descent' (NQIBD) approach, which allowed us to identify the mutation causing the disease by sequencing DNA from a single unaffected homozygous parent. We show that CCFDN is caused by a single-nucleotide substitution in an antisense Alu element in intron 6 of CTDP1 (encoding the protein phosphatase FCP1, an essential component of the eukaryotic transcription machinery5,6), resulting in a rare mechanism of aberrant splicing and an Alu insertion in the processed mRNA. CCFDN thus joins the group of 'transcription syndromes'7 and is the first 'purely' transcriptional defect identified that affects polymerase II–mediated gene expression.

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Figure 1: Fine mapping of the gene associated with CCFDN on 18qter.
Figure 2: NQIBD analysis.
Figure 3: The only difference between NQIBD chromosomes is a single-nucleotide substitution in an intronic Alu element.
Figure 4: The Alu C→T mutation causes aberrant splicing of CTDP1.

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Acknowledgements

We thank affected individuals and their families for participating in this project; A. Corches, C. Lupu, M. Molnar, A. Kelemen, P. Seeman, V. Milic-Rasic for referring individuals with CCFDN; M. Delatycki, K. Jones, J. Colomer and T. Ishikawa for referring individuals with MSS; K. Sperling and J. Kunze for supporting this study; J. Reeve for help with the DMLE+ software; A. Usheva for discussions; N. Laing for critical comments on the manuscript; and D. Chandler and I. Martins for technical help. The study was funded by the National Health and Medical Research Council of Australia, The Wellcome Trust, the Australian Research Council, the Deutsche Forschungsgemeinschaft and partly by the German Ministry of Education and Research.

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Author notes

  1. Raymonda Varon and Rebecca Gooding: These two authors contributed equally to this work.

Authors and Affiliations

  1. Institute of Human Genetics, Charité, Humboldt University, Berlin, Germany

    Raymonda Varon, Christina Steglich, Petra Ambrugger, Anke Reinhold, Luitgard Neumann & Joachim Bürger

  2. Laboratory of Molecular Genetics, Western Australian Institute for Medical Research, University of Western Australia Centre for Medical Research, Perth, Australia

    Rebecca Gooding, Lorna Marns, Dora Angelicheva, Kiau Kiun Yong, Bharti Morar & Luba Kalaydjieva

  3. Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA

    Hua Tang

  4. Department of Neuropediatrics, Charité, Humboldt University, Berlin, Germany

    Anke Reinhold & Arpad von Moers

  5. Department of Neurology, Academic Medical Centre, University of Amsterdam, The Netherlands

    Frank Baas & Marcel Kwa

  6. Department of Neurology, Medical University, Sofia, Bulgaria

    Ivailo Tournev & Velina Guerguelcheva

  7. Laboratory of Molecular Pathology, Medical University, Sofia, Bulgaria

    Ivo Kremensky

  8. Friedrich-Baur Institut, Ludwig-Maximilians-Universität, München, Germany

    Hanns Lochmüller & Maggie Walter

  9. Department of Ophthalmology, University Hospital of Vienna, Austria

    Andrea Müllner-Eidenböck

  10. Istituto Ortopedico Rizzoli, Bologna, Italy

    Luciano Merlini

  11. Munich Re, Centre of Competence Biosciences, Munich, Germany

    Joachim Bürger

  12. University of Utah School of Medicine, Salt Lake City, Utah, USA

    Kathryn Swoboda

  13. Institute of Neurology and National Hospital for Neurology and Neurosurgery, London, UK

    P K Thomas

  14. Department of Genetics, Stanford University School of Medicine, Stanford, California, USA

    Neil Risch

  15. Division of Research, Kaiser Permanente, Oakland, California, USA

    Neil Risch

Authors
  1. Raymonda Varon
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Correspondence to Luba Kalaydjieva.

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Varon, R., Gooding, R., Steglich, C. et al. Partial deficiency of the C-terminal-domain phosphatase of RNA polymerase II is associated with congenital cataracts facial dysmorphism neuropathy syndrome. Nat Genet 35, 185–189 (2003). https://doi.org/10.1038/ng1243

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