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Author(s):
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Hsia, Gabriella S. P.
[1]
;
Musso, Camila M.
[1]
;
Alvizi, Lucas
[1]
;
Brito, Luciano A.
[1]
;
Kobayashi, Gerson S.
[1]
;
Pavanello, Rita C. M.
[1]
;
Zatz, Mayana
[1]
;
Gardham, Alice
[2]
;
Wakeling, Emma
[2]
;
Zechi-Ceide, Roseli M.
[3]
;
Bertola, Debora
[1, 4]
;
Passos-Bueno, Maria Rita
[1]
Total Authors: 12
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| Affiliation: | [1] Univ Sao Paulo, Inst Biociencias, Dept Genet & Biol Evolut, Ctr Estudos Genoma Humano & Celulas Tronco, Sao Paulo - Brazil
[2] Great Ormond St Hosp Sick Children, North East Thames Genet Serv, London - England
[3] Univ Sao Paulo, Hosp Reabilitacao Anomalias Craniofaciais, Sao Paulo - Brazil
[4] Univ Sao Paulo, FMUSP, Hosp Clin, Inst Crianca, Sao Paulo - Brazil
Total Affiliations: 4
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| Document type: |
Journal article
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| Source: |
FRONTIERS IN GENETICS;
v. 9,
APR 25 2018.
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| Web of Science Citations: |
0
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| Abstract |
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 0 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. (AU) |
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| FAPESP's process: |
13/08028-1 - CEGH-CEL - Human Genome and Stem Cell Research Center
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| Grantee: | Mayana Zatz |
| Support type: |
Research Grants - Research, Innovation and Dissemination Centers - RIDC
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| FAPESP's process: |
15/21781-6 - Characterization of EIF4A3 expansions in Brazilian population
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| Grantee: | Gabriella Shih Ping Hsia |
| Support type: |
Scholarships in Brazil - Scientific Initiation
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