1. Partial deficiency of the C-terminal-domain phosphatase of RNA polymerase II is associated with congenital cataracts facial dysmorphism neuropathy syndrome
- Author
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Andrea Müllner-Eidenböck, Dora Angelicheva, Kiau Kiun Yong, Ivailo Tournev, Luba Kalaydjieva, Raymonda Varon, Hua Tang, Luitgard M. Neumann, Luciano Merlini, Petra Ambrugger, Anke Reinhold, Christina Steglich, Frank Baas, Hanns Lochmüller, Velina Guerguelcheva, Kathryn J. Swoboda, Maggie C. Walter, Bharti Morar, P. K. Thomas, Lorna Marns, Marcel S G Kwa, Arpad von Moers, Neil Risch, Rebecca Gooding, Ivo Kremensky, Joachim Burger, and Genome Analysis
- Subjects
Roma ,Molecular Sequence Data ,Alu element ,Genes, Recessive ,RNA polymerase II ,Biology ,Polymerase Chain Reaction ,Cataract ,Conserved sequence ,Phosphoprotein Phosphatases ,Genetics ,medicine ,Humans ,Point Mutation ,Amino Acid Sequence ,Gene ,Conserved Sequence ,Binding Sites ,Base Sequence ,Point mutation ,Haplotype ,Intron ,Chromosome Mapping ,Syndrome ,medicine.disease ,Introns ,Face ,Congenital cataracts ,biology.protein ,RNA Polymerase II ,Nervous System Diseases ,Chromosomes, Human, Pair 18 - 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 mutation(4). 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 machinery(5,6)), 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
- Published
- 2003