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Novel IQCE variations confirm its role in postaxial polydactyly and cause ciliary defect phenotype in zebrafish.
Estrada-Cuzcano, Alejandro; Etard, Christelle; Delvallée, Clarisse; Stoetzel, Corinne; Schaefer, Elise; Scheidecker, Sophie; Geoffroy, Véronique; Schneider, Aline; Studer, Fouzia; Mattioli, Francesca; Chennen, Kirsley; Sigaudy, Sabine; Plassard, Damien; Poch, Olivier; Piton, Amélie; Strahle, Uwe; Muller, Jean; Dollfus, Hélène.
Afiliación
  • Estrada-Cuzcano A; Laboratoire de Génétique médicale, UMR_S INSERM U1112, IGMA, Faculté de Médecine, FMTS, Université de Strasbourg, Strasbourg, France.
  • Etard C; Institute of Toxicology and Genetics (ITG), Karlsruhe Institute of Technology (KIT), Karlsruhe, Eggenstein-Leopoldshafen, Germany.
  • Delvallée C; Laboratoire de Génétique médicale, UMR_S INSERM U1112, IGMA, Faculté de Médecine, FMTS, Université de Strasbourg, Strasbourg, France.
  • Stoetzel C; Laboratoire de Génétique médicale, UMR_S INSERM U1112, IGMA, Faculté de Médecine, FMTS, Université de Strasbourg, Strasbourg, France.
  • Schaefer E; Laboratoire de Génétique médicale, UMR_S INSERM U1112, IGMA, Faculté de Médecine, FMTS, Université de Strasbourg, Strasbourg, France.
  • Scheidecker S; Service de Génétique Médicale, Institut de Génétique Médicale d'Alsace, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.
  • Geoffroy V; Laboratoire de Génétique médicale, UMR_S INSERM U1112, IGMA, Faculté de Médecine, FMTS, Université de Strasbourg, Strasbourg, France.
  • Schneider A; Laboratoires de Diagnostic Génétique, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.
  • Studer F; Laboratoire de Génétique médicale, UMR_S INSERM U1112, IGMA, Faculté de Médecine, FMTS, Université de Strasbourg, Strasbourg, France.
  • Mattioli F; Laboratoire de Génétique médicale, UMR_S INSERM U1112, IGMA, Faculté de Médecine, FMTS, Université de Strasbourg, Strasbourg, France.
  • Chennen K; Centre de Référence pour les affections rares en génétique ophtalmologique, CARGO, Filière SENSGENE, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.
  • Sigaudy S; Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch-Graffenstaden, France.
  • Plassard D; Institut de Génétique et de Biologie Moléculaire et Cellulaire, INSERM U1258, Illkirch-Graffenstaden, France.
  • Poch O; Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS UMR 7104, Illkirch-Graffenstaden, France.
  • Piton A; Institut de Génétique et de Biologie Moléculaire et Cellulaire, Université de Strasbourg, Illkirch, France.
  • Strahle U; Laboratoire de Génétique médicale, UMR_S INSERM U1112, IGMA, Faculté de Médecine, FMTS, Université de Strasbourg, Strasbourg, France.
  • Muller J; Complex Systems and Translational Bioinformatics, ICube UMR 7357, Fédération de Médecine Translationnelle, Université de Strasbourg, Strasbourg, France.
  • Dollfus H; Département de Génétique Médicale, Hôpital de la Timone, Marseille, France.
Hum Mutat ; 41(1): 240-254, 2020 01.
Article en En | MEDLINE | ID: mdl-31549751
Polydactyly is one of the most frequent inherited defects of the limbs characterized by supernumerary digits and high-genetic heterogeneity. Among the many genes involved, either in isolated or syndromic forms, eight have been implicated in postaxial polydactyly (PAP). Among those, IQCE has been recently identified in a single consanguineous family. Using whole-exome sequencing in patients with uncharacterized ciliopathies, including PAP, we identified three families with biallelic pathogenic variations in IQCE. Interestingly, the c.895_904del (p.Val301Serfs*8) was found in all families without sharing a common haplotype, suggesting a recurrent mechanism. Moreover, in two families, the systemic phenotype could be explained by additional pathogenic variants in known genes (TULP1, ATP6V1B1). RNA expression analysis on patients' fibroblasts confirms that the dysfunction of IQCE leads to the dysregulation of genes associated with the hedgehog-signaling pathway, and zebrafish experiments demonstrate a full spectrum of phenotypes linked to defective cilia: Body curvature, kidney cysts, left-right asymmetry, misdirected cilia in the pronephric duct, and retinal defects. In conclusion, we identified three additional families confirming IQCE as a nonsyndromic PAP gene. Our data emphasize the importance of taking into account the complete set of variations of each individual, as each clinical presentation could finally be explained by multiple genes.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Fenotipo / Variación Genética / Dedos del Pie / Polidactilia / Predisposición Genética a la Enfermedad / Péptidos y Proteínas de Señalización Intracelular / Dedos / Ciliopatías / Proteínas de la Membrana Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Revista: Hum Mutat Asunto de la revista: GENETICA MEDICA Año: 2020 Tipo del documento: Article País de afiliación: Francia Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Fenotipo / Variación Genética / Dedos del Pie / Polidactilia / Predisposición Genética a la Enfermedad / Péptidos y Proteínas de Señalización Intracelular / Dedos / Ciliopatías / Proteínas de la Membrana Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Revista: Hum Mutat Asunto de la revista: GENETICA MEDICA Año: 2020 Tipo del documento: Article País de afiliación: Francia Pais de publicación: Estados Unidos