A Noncoding Expansion in EIF4A3 Causes Richieri-Costa-Pereira Syndrome, a Craniofacial Disorder Associated with Limb Defects

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  • Francine P Favaro, Departamento de Genética Clínica, Hospital de Reabilitação de Anomalias Craniofaciais, Universidade de São Paulo (HRAC-USP), 17012-090, Bauru, São Paulo, Brasil.
  • ,
  • Lucas Alvizi, Centro de Estudos do Genoma Humano, Instituto de Biociências, Universidade de São Paulo, 05508-090, São Paulo, São Paulo, Brasil.
  • ,
  • Roseli M Zechi-Ceide, Departamento de Genética Clínica, Hospital de Reabilitação de Anomalias Craniofaciais, Universidade de São Paulo (HRAC-USP), 17012-090, Bauru, São Paulo, Brasil.
  • ,
  • Debora Bertola, Centro de Estudos do Genoma Humano, Instituto de Biociências, Universidade de São Paulo, 05508-090, São Paulo, São Paulo, Brasil.
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  • Temis M Felix, Hospital das Clínicas de Porto Alegre, Departamento de Genética, Universidade Federal do Rio Grande do Sul, 90035-903, Porto Alegre, Rio Grande do Sul, Brasil.
  • ,
  • Josiane de Souza, Centro de Atendimento Integral ao Fissurado Lábio Palatal, 80150-000, Curitiba, Paraná, Brasil.
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  • Salmo Raskin, Núcleo de Investigação Molecular Avançada, Centro de Ciências Biológicas e da Saúde, Pontifícia Universidade Católica do Paraná, 80150-000, Curitiba, Paraná, Brasil.
  • ,
  • Stephen R F Twigg, Clinical Genetics Group, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK.
  • ,
  • Andrea M J Weiner, Instituto de Biología Molecular y Celular de Rosario (IBR), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET) - Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, S2000FHQ, Rosario, Argentina.
  • ,
  • Pablo Armas, Instituto de Biología Molecular y Celular de Rosario (IBR), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET) - Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, S2000FHQ, Rosario, Argentina.
  • ,
  • Ezequiel Margarit, Instituto de Biología Molecular y Celular de Rosario (IBR), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET) - Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, S2000FHQ, Rosario, Argentina.
  • ,
  • Nora B Calcaterra, Instituto de Biología Molecular y Celular de Rosario (IBR), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET) - Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, S2000FHQ, Rosario, Argentina.
  • ,
  • Gregers Rom Andersen
  • Simon J McGowan, Computational Biology Research Group, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK.
  • ,
  • Andrew O M Wilkie, Clinical Genetics Group, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK.
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  • Antonio Richieri-Costa, Departamento de Genética Clínica, Hospital de Reabilitação de Anomalias Craniofaciais, Universidade de São Paulo (HRAC-USP), 17012-090, Bauru, São Paulo, Brasil.
  • ,
  • Maria L G de Almeida, Departamento de Genética Clínica, Hospital de Reabilitação de Anomalias Craniofaciais, Universidade de São Paulo (HRAC-USP), 17012-090, Bauru, São Paulo, Brasil.
  • ,
  • Maria Rita Passos-Bueno, Centro de Estudos do Genoma Humano, Instituto de Biociências, Universidade de São Paulo, 05508-090, São Paulo, São Paulo, Brasil. Electronic address: passos@ib.usp.br.
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 5' untranslated region (5' 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 RCPS-affected 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.
Original languageEnglish
JournalAmerican Journal of Human Genetics
Volume94
Issue1
Pages (from-to)120-128
Number of pages9
ISSN0002-9297
DOIs
Publication statusPublished - 19 Dec 2013

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