1. A Noncoding Expansion in EIF4A3 Causes Richieri-Costa-Pereira Syndrome, a Craniofacial Disorder Associated with Limb Defects
- Author
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Francine Pinheiro Favaro, Ezequiel Margarit, Josiane Souza, Antonio Richieri-Costa, Andrea M.J. Weiner, Stephen R.F. Twigg, Pablo Armas, Lucas Alvizi, Simon J. McGowan, Maria Leine Guion de Almeida, Salmo Raskin, Nora B. Calcaterra, Andrew O.M. Wilkie, Roseli Maria Zechi-Ceide, Têmis Maria Félix, Gregers R. Andersen, Débora Romeo Bertola, and Maria Rita Passos-Bueno
- Subjects
Untranslated region ,Male ,Richieri-Costa-Pereira Syndrome ,Protein Conformation ,Craniofacial Disorder ,DEAD-box RNA Helicases ,0302 clinical medicine ,Noncoding Expansion ,Missense mutation ,Genetics(clinical) ,Child ,Zebrafish ,Genetics (clinical) ,Genetics ,0303 health sciences ,Pierre Robin Syndrome ,Chromosome Mapping ,purl.org/becyt/ford/3.1 [https] ,Medicina Básica ,Clubfoot ,Child, Preschool ,Female ,purl.org/becyt/ford/3 [https] ,Limb morphogenesis ,Hand Deformities, Congenital ,Eif4a3 ,CIENCIAS MÉDICAS Y DE LA SALUD ,Molecular Sequence Data ,Genética Humana ,Mutation, Missense ,Biology ,Bone and Bones ,03 medical and health sciences ,Report ,Limb Defects ,medicine ,Animals ,Humans ,Amino Acid Sequence ,Craniofacial ,Allele ,Gene ,Alleles ,030304 developmental biology ,Dysostosis ,medicine.disease ,biology.organism_classification ,Eukaryotic Initiation Factor-4A ,030217 neurology & neurosurgery - Abstract
Richieri-Costa-Pereira syndrome is an autosomal-recessive acrofacial dysostosis characterized by mandibular median cleft associated with other craniofacial anomalies and severe limb defects. Learning and language disabilities are also prevalent. We mapped the mutated gene to a 122 kb region at 17q25.3 through identity-by-descent analysis in 17 genealogies. Sequencing strategies identified an expansion of a region with several repeats of 18- or 20-nucleotide motifs in the 50 untranslated region (50 UTR) of EIF4A3, which contained from 14 to 16 repeats in the affected individuals and from 3 to 12 repeats in 520 healthy individuals. A missense substitution of a highly conserved residue likely to affect the interaction of eIF4AIII with the UPF3B subunit of the exon junction complex in trans with an expanded allele was found in an unrelated individual with an atypical presentation, thus expanding mutational mechanisms and phenotypic diversity of RCPS. EIF4A3 transcript abundance was reduced in both white blood cells and mesenchymal cells of RCPSaffected individuals as compared to controls. Notably, targeting the orthologous eif4a3 in zebrafish led to underdevelopment of several craniofacial cartilage and bone structures, in agreement with the craniofacial alterations seen in RCPS. Our data thus suggest that RCPS is caused by mutations in EIF4A3 and show that EIF4A3, a gene involved in RNA metabolism, plays a role in mandible, laryngeal, and limb morphogenesis Fil: Favaro, Francine P.. Universidade de Sao Paulo; Brasil Fil: Alvizi, Lucas. Universidade de Sao Paulo; Brasil Fil: Zechi Ceide, Roseli M.. Universidade de Sao Paulo; Brasil Fil: Bertola, Debora. Universidade de Sao Paulo; Brasil Fil: Felix, Temis M.. Universidade Federal do Rio Grande do Sul; Brasil Fil: de Souza, Josiane. Centro de Atendimento Integral ao Fissurado Lábio Palatal; Brasil Fil: Raskin, Salmo. Pontificia Universidade Católica do Parana; Brasil Fil: Twigg, Stephen R. F.. University of Oxford; Reino Unido Fil: Weiner, Andrea Maria Julia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Biología Molecular y Celular de Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario; Argentina Fil: Armas, Pablo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Biología Molecular y Celular de Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario; Argentina Fil: Margarit, Ezequiel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Biología Molecular y Celular de Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario; Argentina Fil: Calcaterra, Nora Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Biología Molecular y Celular de Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario; Argentina Fil: Andersen, Gregers R.. Aarhus University; Dinamarca Fil: McGowan, Simon. University of Oxford; Reino Unido Fil: Wilkie, Andrew O. M.. University of Oxford; Reino Unido Fil: Richieri Costa, Antonio. Universidade de Sao Paulo; Brasil Fil: de Almeida, Maria L. G.. Universidade de Sao Paulo; Brasil Fil: Passos Bueno, Maria Rita. Universidade de Sao Paulo; Brasil
- Published
- 2014
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