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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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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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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DOI: https://doi.org/10.1038/ng1243
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