title: A noncoding expansion in EIF4A3 causes Richieri-Costa-Pereira syndrome, a craniofacial disorder associated with limb defects.
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.
authors.affiliation: Departamento de Genética Clínica, Hospital de Reabilitação de Anomalias Craniofaciais, Universidade de São Paulo (HRAC-USP), 17012-090, Bauru, São Paulo, Brasil.
authors.forename: Francine P
authors.initials: FP
authors.lastname: Favaro
authors.affiliation: Centro de Estudos do Genoma Humano, Instituto de Biociências, Universidade de São Paulo, 05508-090, São Paulo, São Paulo, Brasil.
authors.forename: Lucas
authors.initials: L
authors.lastname: Alvizi
authors.affiliation: Departamento de Genética Clínica, Hospital de Reabilitação de Anomalias Craniofaciais, Universidade de São Paulo (HRAC-USP), 17012-090, Bauru, São Paulo, Brasil.
authors.forename: Roseli M
authors.initials: RM
authors.lastname: Zechi-Ceide
authors.affiliation: Centro de Estudos do Genoma Humano, Instituto de Biociências, Universidade de São Paulo, 05508-090, São Paulo, São Paulo, Brasil.
authors.forename: Debora
authors.initials: D
authors.lastname: Bertola
authors.affiliation: 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.
authors.forename: Temis M
authors.initials: TM
authors.lastname: Felix
authors.affiliation: Centro de Atendimento Integral ao Fissurado Lábio Palatal, 80150-000, Curitiba, Paraná, Brasil.
authors.forename: Josiane
authors.initials: J
authors.lastname: de Souza
authors.affiliation: Núcleo de Investigação Molecular Avançada, Centro de Ciências Biológicas e da Saúde, Pontifícia Universidade Católica do Paraná, 80150-000, Curitiba, Paraná, Brasil.
authors.forename: Salmo
authors.initials: S
authors.lastname: Raskin
authors.affiliation: Clinical Genetics Group, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK.
authors.forename: Stephen R F
authors.initials: SR
authors.lastname: Twigg
authors.affiliation: 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.
authors.forename: Andrea M J
authors.initials: AM
authors.lastname: Weiner
authors.affiliation: 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.
authors.forename: Pablo
authors.initials: P
authors.lastname: Armas
authors.affiliation: 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.
authors.forename: Ezequiel
authors.initials: E
authors.lastname: Margarit
authors.affiliation: 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.
authors.forename: Nora B
authors.initials: NB
authors.lastname: Calcaterra
authors.affiliation: Department of Molecular Biology and Genetics. Aarhus University, Gustav Wieds Vej 10C, 8000 Aarhus, Denmark.
authors.forename: Gregers R
authors.initials: GR
authors.lastname: Andersen
authors.affiliation: Computational Biology Research Group, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK.
authors.forename: Simon J
authors.initials: SJ
authors.lastname: McGowan
authors.affiliation: Clinical Genetics Group, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK.
authors.forename: Andrew O M
authors.initials: AO
authors.lastname: Wilkie
authors.affiliation: Departamento de Genética Clínica, Hospital de Reabilitação de Anomalias Craniofaciais, Universidade de São Paulo (HRAC-USP), 17012-090, Bauru, São Paulo, Brasil.
authors.forename: Antonio
authors.initials: A
authors.lastname: Richieri-Costa
authors.affiliation: Departamento de Genética Clínica, Hospital de Reabilitação de Anomalias Craniofaciais, Universidade de São Paulo (HRAC-USP), 17012-090, Bauru, São Paulo, Brasil.
authors.forename: Maria L G
authors.initials: ML
authors.lastname: de Almeida
authors.affiliation: 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.
authors.forename: Maria Rita
authors.initials: MR
authors.lastname: Passos-Bueno
mesh_terms: D000483:Alleles; D000595:Amino Acid Sequence; D000818:Animals; D001842:Bone and Bones / Q000002:abnormalities; D002648:Child; D002675:Child, Preschool; D002874:Chromosome Mapping; D003025:Clubfoot / Q000235:genetics*; D053487:DEAD-box RNA Helicases / Q000235:genetics* / Q000378:metabolism; D039601:Eukaryotic Initiation Factor-4A / Q000235:genetics* / Q000378:metabolism; D005260:Female; D006228:Hand Deformities, Congenital / Q000235:genetics*; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010855:Pierre Robin Syndrome / Q000235:genetics*; D011487:Protein Conformation; D015027:Zebrafish / Q000002:abnormalities
chemical_list: D039601:Eukaryotic Initiation Factor-4A; C403493:EIF4A3 protein, human; D053487:DEAD-box RNA Helicases