2. Academic Validation
  3. A noncoding expansion in EIF4A3 causes Richieri-Costa-Pereira syndrome, a craniofacial disorder associated with limb defects

A noncoding expansion in EIF4A3 causes Richieri-Costa-Pereira syndrome, a craniofacial disorder associated with limb defects

  • Am J Hum Genet. 2014 Jan 2;94(1):120-8. doi: 10.1016/j.ajhg.2013.11.020.
Francine P Favaro 1,  Lucas Alvizi 2,  Roseli M Zechi-Ceide 1,  Debora Bertola 2,  Temis M Felix 3,  Josiane de Souza 4,  Salmo Raskin 5,  Stephen R F Twigg 6,  Andrea M J Weiner 7,  Pablo Armas 7,  Ezequiel Margarit 7,  Nora B Calcaterra 7,  Gregers R Andersen 8,  Simon J McGowan 9,  Andrew O M Wilkie 6,  Antonio Richieri-Costa 1,  Maria L G de Almeida 1,  Maria Rita Passos-Bueno 10
Affiliations

Affiliations

  • 1 Departamento de Genética Clínica, Hospital de Reabilitação de Anomalias Craniofaciais, Universidade de São Paulo (HRAC-USP), 17012-090, Bauru, São Paulo, Brasil.
  • 2 Centro de Estudos do Genoma Humano, Instituto de Biociências, Universidade de São Paulo, 05508-090, São Paulo, São Paulo, Brasil.
  • 3 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.
  • 4 Centro de Atendimento Integral ao Fissurado Lábio Palatal, 80150-000, Curitiba, Paraná, Brasil.
  • 5 Núcleo de Investigação Molecular Avançada, Centro de Ciências Biológicas e da Saúde, Pontifícia Universidade Católica do Paraná, 80150-000, Curitiba, Paraná, Brasil.
  • 6 Clinical Genetics Group, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK.
  • 7 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.
  • 8 Department of Molecular Biology and Genetics. Aarhus University, Gustav Wieds Vej 10C, 8000 Aarhus, Denmark.
  • 9 Computational Biology Research Group, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK.
  • 10 Centro de Estudos do Genoma Humano, Instituto de Biociências, Universidade de São Paulo, 05508-090, São Paulo, São Paulo, Brasil. Electronic address: [email protected].
PMID: 24360810 DOI: 10.1016/j.ajhg.2013.11.020
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 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.

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