title: Autosomal recessive POLR1D mutation with decrease of TCOF1 mRNA is responsible for Treacher Collins syndrome.
abstract: OBJECTIVE
  Treacher Collins syndrome is a mandibulofacial dysostosis caused by mutations in genes involved in ribosome biogenesis and synthesis. TCOF1 mutations are observed in ~80% of the patients and are inherited in an autosomal dominant manner. Recently, two other genes have been reported in <2% of patients--POLR1D in patients with autosomal dominant inheritance, and POLR1C in patients with autosomal recessive inheritance.
  
  
  METHODS
  We performed direct sequencing of TCOF1, POLR1C, and POLR1D in two unrelated consanguineous families.
  
  
  RESULTS
  The four affected children shared the same homozygous mutation in POLR1D (c.163C>G, p.Leu55Val). This mutation is localized in a region encoding the dimerization domain of the RNA polymerase. It is supposed that this mutation impairs RNA polymerase, resulting in a lower amount of mature dimeric ribosomes. A functional analysis of the transcripts of TCOF1 by real-time quantitative reverse transcription-polymerase chain reaction was performed in the first family, demonstrating a 50% reduction in the index case, compatible with this hypothesis.
  
  
  CONCLUSIONS
  This is the first report of POLR1D mutation being responsible for an autosomal recessive inherited Treacher Collins syndrome. These results reinforce the concept of genetic heterogeneity of Treacher Collins syndrome and underline the importance of combining clinical expertise and familial molecular analyses for appropriate genetic counseling.
authors.affiliation: 1] Service de Génétique Médicale, Hôpitaux Universitaires de Strasbourg, CHU de Hautepierre, Strasbourg, France [2] Laboratoire de Génétique Médicale, INSERM U1112, Faculté de Médecine, Université de Strasbourg, Strasbourg, France.
authors.forename: Elise
authors.initials: E
authors.lastname: Schaefer
authors.affiliation: Service de Biochimie et de Biologie Moleculaire, Hôpital Lariboisière, INSERM U606, Assistance Publique-Hôpitaux de Paris, Paris, France.
authors.forename: Corinne
authors.initials: C
authors.lastname: Collet
authors.affiliation: Service de Génétique Médicale, CHRU Montpellier, Université de Montpellier 1, Montpellier, France.
authors.forename: David
authors.initials: D
authors.lastname: Genevieve
authors.affiliation: Service de Génétique Médicale, CHRU Montpellier, Université de Montpellier 1, Montpellier, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Vincent
authors.affiliation: Institut für Humangenetik, Universitätsklinikum Essen, Universität Duisburg-Essen, Essen, Germany.
authors.forename: Dietmar R
authors.initials: DR
authors.lastname: Lohmann
authors.affiliation: Service de Génétique Médicale, CHRU Montpellier, Université de Montpellier 1, Montpellier, France.
authors.forename: Elodie
authors.initials: E
authors.lastname: Sanchez
authors.affiliation: Service de Pédiatrie, Centre Hospitalier de Haguenau, Haguenau, France.
authors.forename: Chantal
authors.initials: C
authors.lastname: Bolender
authors.affiliation: Service ORL, Hôpitaux Universitaires de Strasbourg, CHU de Hautepierre, Strasbourg, France.
authors.forename: Marie-Madeleine
authors.initials: MM
authors.lastname: Eliot
authors.affiliation: Center for Genomics, University of Cologne, Cologne, Germany.
authors.forename: Gudrun
authors.initials: G
authors.lastname: Nürnberg
authors.affiliation: Department of Genetics and Evolutive Biology, Human Genome Center, Institute of Bioscience, University of Sao Paulo, Sao Paulo, Brazil.
authors.forename: Maria-Rita
authors.initials: MR
authors.lastname: Passos-Bueno
authors.affiliation: Institut für Humangenetik, Universitätsklinikum Essen, Universität Duisburg-Essen, Essen, Germany.
authors.forename: Dagmar
authors.initials: D
authors.lastname: Wieczorek
authors.affiliation: Centre de Génétique Humaine, Université de Franche-Comté, Besançon, France.
authors.forename: Lionel
authors.initials: L
authors.lastname: van Maldergem
authors.affiliation: 1] Service de Génétique Médicale, Hôpitaux Universitaires de Strasbourg, CHU de Hautepierre, Strasbourg, France [2] Laboratoire de Génétique Médicale, INSERM U1112, Faculté de Médecine, Université de Strasbourg, Strasbourg, France [3] Current affiliation: Service de Génétique, CHU la Réunion, Hôpital Félix Guyon, Saint-Denis, France.
authors.forename: Bérénice
authors.initials: B
authors.lastname: Doray
mesh_terms: D000328:Adult; D019943:Amino Acid Substitution; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D012321:DNA-Directed RNA Polymerases / Q000235:genetics*; D019066:Facies; D005260:Female; D005786:Gene Expression Regulation; D005808:Genes, Recessive; D056726:Genetic Association Studies; D056426:Genetic Loci; D006239:Haplotypes; D006720:Homozygote; D006801:Humans; D008342:Mandibulofacial Dysostosis / Q000175:diagnosis* / Q000235:genetics*; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics*; D010641:Phenotype; D010750:Phosphoproteins / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics*
chemical_list: D009687:Nuclear Proteins; D010750:Phosphoproteins; D012333:RNA, Messenger; C105442:TCOF1 protein, human; D012321:DNA-Directed RNA Polymerases; C569282:POLR1D protein, human