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Screening of TCOF1 in patients from different populations: confirmation of mutational hot spots and identification of a novel missense mutation that suggests an important functional domain in the protein treacle
  1. A Splendore1,
  2. E W Jabs2,
  3. M R Passos-Bueno1
  1. 1Centro de Estudos do Genoma Humano, Departamento de Genética, Instituto de Biociências Universidade de São Paulo, São Paulo, SP, Brazil
  2. 2Department of Pediatrics, Medicine, and Surgery, Center for Medical Genetics, Johns Hopkins University School of Medicine, Baltimore, MD, USA
  1. Correspondence to:
 Dr M R Passos-Bueno, Departamento de Genética, Instituto de Biociências, Universidade de São Paulo, Rua do Matão 277, CEP 05508-900, Cidade Universitária, São Paulo, SP, Brazil;

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Treacher Collins syndrome (TCS, MIM *154500) is an autosomal dominant craniofacial disorder characterised by malar hypoplasia, micrognathia, downward slanting palpebral fissures, lower eyelid coloboma, malformed auricles, conductive deafness, and cleft palate. The estimated incidence is 1/50 000, with 60% of the cases resulting from sporadic mutations.1 There is marked phenotypic variability among patients, ranging from perinatal death because of a compromised airway to those that go undetected by medical examination. The gene underlying this condition, TCOF1, was mapped in 19962 and since then mutation detection studies have concluded that: (1) the majority of pathogenic mutations are small deletions and insertions causing frameshifts that are predicted to result in a truncated protein; (2) mutations (both polymorphic and pathogenic) can be found throughout the 25 coding exons of the gene; (3) most mutations are family specific with the exception of a commonly occurring 5 bp deletion in exon 24 (found in approximately 16% of families); and (4) there is no correlation between type and/or localisation of the mutation and phenotypic expression.3–6 Furthermore, the observation that more than 50% of all described pathogenic mutations known to date are clustered in five exons (10, 15, 16, 23, and 24) has led to the hypothesis that these five exons are mutational hot spots, suggesting that any effort to identify mutations in TCOF1 would benefit from testing these five exons before extending the analysis to the rest of the gene.6

The protein encoded by the TCOF1 gene, treacle, has repetitive motifs encoded by exons 7-16, which are subject to phosphorylation by casein kinase II7 and a nucleolar localisation signal on its C-terminus.8 It bears weak similarity to a family of nucleolar phosphoproteins and its precise function remains unknown.9,10 In the present work, screening for TCOF1 mutations …

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