Complexity of the 5′ Untranslated Region of EIF4A3, a Critical Factor for Craniofacial and Neural Development
Repeats in coding and non-coding regions have increasingly been associated with many human genetic disorders, such as Richieri-Costa-Pereira syndrome (RCPS). RCPS, mostly characterized by midline cleft mandible, Robin sequence and limb defects, is an autosomal-recessive acrofacial dysostosis mainly...
| Main Authors: | , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2018-04-01
|
| Series: | Frontiers in Genetics |
| Subjects: | |
| Online Access: | http://journal.frontiersin.org/article/10.3389/fgene.2018.00149/full |
| _version_ | 1828446469290459136 |
|---|---|
| author | Gabriella S. P. Hsia Camila M. Musso Lucas Alvizi Luciano A. Brito Gerson S. Kobayashi Rita C. M. Pavanello Mayana Zatz Alice Gardham Emma Wakeling Roseli M. Zechi-Ceide Debora Bertola Debora Bertola Maria Rita Passos-Bueno |
| author_facet | Gabriella S. P. Hsia Camila M. Musso Lucas Alvizi Luciano A. Brito Gerson S. Kobayashi Rita C. M. Pavanello Mayana Zatz Alice Gardham Emma Wakeling Roseli M. Zechi-Ceide Debora Bertola Debora Bertola Maria Rita Passos-Bueno |
| author_sort | Gabriella S. P. Hsia |
| collection | DOAJ |
| description | Repeats in coding and non-coding regions have increasingly been associated with many human genetic disorders, such as Richieri-Costa-Pereira syndrome (RCPS). RCPS, mostly characterized by midline cleft mandible, Robin sequence and limb defects, is an autosomal-recessive acrofacial dysostosis mainly reported in Brazilian patients. This disorder is caused by decreased levels of EIF4A3, mostly due to an increased number of repeats at the EIF4A3 5′UTR. EIF4A3 5′UTR alleles are CG-rich and vary in size and organization of three types of motifs. An exclusive allelic pattern was identified among affected individuals, in which the CGCA-motif is the most prevalent, herein referred as “disease-associated CGCA-20nt motif.” The origin of the pathogenic alleles containing the disease-associated motif, as well as the functional effects of the 5′UTR motifs on EIF4A3 expression, to date, are entirely unknown. Here, we characterized 43 different EIF4A3 5′UTR alleles in a cohort of 380 unaffected individuals. We identified eight heterozygous unaffected individuals harboring the disease-associated CGCA-20nt motif and our haplotype analyses indicate that there are more than one haplotype associated with RCPS. The combined analysis of number, motif organization and haplotypic diversity, as well as the observation of two apparently distinct haplotypes associated with the disease-associated CGCA-20nt motif, suggest that the RCPS alleles might have arisen from independent unequal crossing-over events between ancient alleles at least twice. Moreover, we have shown that the number and sequence of motifs in the 5′UTR region is associated with EIF4A3 repression, which is not mediated by CpG methylation. In conclusion, this study has shown that the large number of repeats in EIF4A3 does not represent a dynamic mutation and RCPS can arise in any population harboring alleles with the CGCA-20nt motif. We also provided further evidence that EIF4A3 5′UTR is a regulatory region and the size and sequence type of the repeats at 5′UTR may contribute to clinical variability in RCPS. |
| first_indexed | 2024-12-10T22:11:47Z |
| format | Article |
| id | doaj.art-80bff2cc0c414e4aa2074f821e695a5d |
| institution | Directory Open Access Journal |
| issn | 1664-8021 |
| language | English |
| last_indexed | 2024-12-10T22:11:47Z |
| publishDate | 2018-04-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Genetics |
| spelling | doaj.art-80bff2cc0c414e4aa2074f821e695a5d2022-12-22T01:31:34ZengFrontiers Media S.A.Frontiers in Genetics1664-80212018-04-01910.3389/fgene.2018.00149362277Complexity of the 5′ Untranslated Region of EIF4A3, a Critical Factor for Craniofacial and Neural DevelopmentGabriella S. P. Hsia0Camila M. Musso1Lucas Alvizi2Luciano A. Brito3Gerson S. Kobayashi4Rita C. M. Pavanello5Mayana Zatz6Alice Gardham7Emma Wakeling8Roseli M. Zechi-Ceide9Debora Bertola10Debora Bertola11Maria Rita Passos-Bueno12Centro de Estudos do Genoma Humano e Células Tronco, Departamento de Genética e Biologia Evolutiva, Instituto de Biociências, Universidade de São Paulo, São Paulo, BrazilCentro de Estudos do Genoma Humano e Células Tronco, Departamento de Genética e Biologia Evolutiva, Instituto de Biociências, Universidade de São Paulo, São Paulo, BrazilCentro de Estudos do Genoma Humano e Células Tronco, Departamento de Genética e Biologia Evolutiva, Instituto de Biociências, Universidade de São Paulo, São Paulo, BrazilCentro de Estudos do Genoma Humano e Células Tronco, Departamento de Genética e Biologia Evolutiva, Instituto de Biociências, Universidade de São Paulo, São Paulo, BrazilCentro de Estudos do Genoma Humano e Células Tronco, Departamento de Genética e Biologia Evolutiva, Instituto de Biociências, Universidade de São Paulo, São Paulo, BrazilCentro de Estudos do Genoma Humano e Células Tronco, Departamento de Genética e Biologia Evolutiva, Instituto de Biociências, Universidade de São Paulo, São Paulo, BrazilCentro de Estudos do Genoma Humano e Células Tronco, Departamento de Genética e Biologia Evolutiva, Instituto de Biociências, Universidade de São Paulo, São Paulo, BrazilNorth East Thames Genetics Service, Great Ormond Street Hospital, London, United KingdomNorth East Thames Genetics Service, Great Ormond Street Hospital, London, United KingdomHospital de Reabilitação de Anomalias Craniofaciais, Universidade de São Paulo, São Paulo, BrazilCentro de Estudos do Genoma Humano e Células Tronco, Departamento de Genética e Biologia Evolutiva, Instituto de Biociências, Universidade de São Paulo, São Paulo, BrazilInstituto da Criança, Hospital das Clínicas da FMUSP, Universidade de São Paulo, São Paulo, BrazilCentro de Estudos do Genoma Humano e Células Tronco, Departamento de Genética e Biologia Evolutiva, Instituto de Biociências, Universidade de São Paulo, São Paulo, BrazilRepeats in coding and non-coding regions have increasingly been associated with many human genetic disorders, such as Richieri-Costa-Pereira syndrome (RCPS). RCPS, mostly characterized by midline cleft mandible, Robin sequence and limb defects, is an autosomal-recessive acrofacial dysostosis mainly reported in Brazilian patients. This disorder is caused by decreased levels of EIF4A3, mostly due to an increased number of repeats at the EIF4A3 5′UTR. EIF4A3 5′UTR alleles are CG-rich and vary in size and organization of three types of motifs. An exclusive allelic pattern was identified among affected individuals, in which the CGCA-motif is the most prevalent, herein referred as “disease-associated CGCA-20nt motif.” The origin of the pathogenic alleles containing the disease-associated motif, as well as the functional effects of the 5′UTR motifs on EIF4A3 expression, to date, are entirely unknown. Here, we characterized 43 different EIF4A3 5′UTR alleles in a cohort of 380 unaffected individuals. We identified eight heterozygous unaffected individuals harboring the disease-associated CGCA-20nt motif and our haplotype analyses indicate that there are more than one haplotype associated with RCPS. The combined analysis of number, motif organization and haplotypic diversity, as well as the observation of two apparently distinct haplotypes associated with the disease-associated CGCA-20nt motif, suggest that the RCPS alleles might have arisen from independent unequal crossing-over events between ancient alleles at least twice. Moreover, we have shown that the number and sequence of motifs in the 5′UTR region is associated with EIF4A3 repression, which is not mediated by CpG methylation. In conclusion, this study has shown that the large number of repeats in EIF4A3 does not represent a dynamic mutation and RCPS can arise in any population harboring alleles with the CGCA-20nt motif. We also provided further evidence that EIF4A3 5′UTR is a regulatory region and the size and sequence type of the repeats at 5′UTR may contribute to clinical variability in RCPS.http://journal.frontiersin.org/article/10.3389/fgene.2018.00149/fullacrofacial dysostosisnon-coding regionhaplotypeexpansioncrossing-over |
| spellingShingle | Gabriella S. P. Hsia Camila M. Musso Lucas Alvizi Luciano A. Brito Gerson S. Kobayashi Rita C. M. Pavanello Mayana Zatz Alice Gardham Emma Wakeling Roseli M. Zechi-Ceide Debora Bertola Debora Bertola Maria Rita Passos-Bueno Complexity of the 5′ Untranslated Region of EIF4A3, a Critical Factor for Craniofacial and Neural Development Frontiers in Genetics acrofacial dysostosis non-coding region haplotype expansion crossing-over |
| title | Complexity of the 5′ Untranslated Region of EIF4A3, a Critical Factor for Craniofacial and Neural Development |
| title_full | Complexity of the 5′ Untranslated Region of EIF4A3, a Critical Factor for Craniofacial and Neural Development |
| title_fullStr | Complexity of the 5′ Untranslated Region of EIF4A3, a Critical Factor for Craniofacial and Neural Development |
| title_full_unstemmed | Complexity of the 5′ Untranslated Region of EIF4A3, a Critical Factor for Craniofacial and Neural Development |
| title_short | Complexity of the 5′ Untranslated Region of EIF4A3, a Critical Factor for Craniofacial and Neural Development |
| title_sort | complexity of the 5 untranslated region of eif4a3 a critical factor for craniofacial and neural development |
| topic | acrofacial dysostosis non-coding region haplotype expansion crossing-over |
| url | http://journal.frontiersin.org/article/10.3389/fgene.2018.00149/full |
| work_keys_str_mv | AT gabriellasphsia complexityofthe5untranslatedregionofeif4a3acriticalfactorforcraniofacialandneuraldevelopment AT camilammusso complexityofthe5untranslatedregionofeif4a3acriticalfactorforcraniofacialandneuraldevelopment AT lucasalvizi complexityofthe5untranslatedregionofeif4a3acriticalfactorforcraniofacialandneuraldevelopment AT lucianoabrito complexityofthe5untranslatedregionofeif4a3acriticalfactorforcraniofacialandneuraldevelopment AT gersonskobayashi complexityofthe5untranslatedregionofeif4a3acriticalfactorforcraniofacialandneuraldevelopment AT ritacmpavanello complexityofthe5untranslatedregionofeif4a3acriticalfactorforcraniofacialandneuraldevelopment AT mayanazatz complexityofthe5untranslatedregionofeif4a3acriticalfactorforcraniofacialandneuraldevelopment AT alicegardham complexityofthe5untranslatedregionofeif4a3acriticalfactorforcraniofacialandneuraldevelopment AT emmawakeling complexityofthe5untranslatedregionofeif4a3acriticalfactorforcraniofacialandneuraldevelopment AT roselimzechiceide complexityofthe5untranslatedregionofeif4a3acriticalfactorforcraniofacialandneuraldevelopment AT deborabertola complexityofthe5untranslatedregionofeif4a3acriticalfactorforcraniofacialandneuraldevelopment AT deborabertola complexityofthe5untranslatedregionofeif4a3acriticalfactorforcraniofacialandneuraldevelopment AT mariaritapassosbueno complexityofthe5untranslatedregionofeif4a3acriticalfactorforcraniofacialandneuraldevelopment |