Publication
Novel deletions and unusual genetic mechanisms underlying alpha-thalassemia
| dc.contributor.author | Ferrão, José | |
| dc.contributor.author | Silva, Marisa | |
| dc.contributor.author | Gonçalves, Lúcia | |
| dc.contributor.author | Gomes, Susana | |
| dc.contributor.author | Coelho, Andreia | |
| dc.contributor.author | Miranda, Armandina | |
| dc.contributor.author | Seuanes, Filomena | |
| dc.contributor.author | Batalha-Reis, Ana | |
| dc.contributor.author | Valtonen-Andrá, C. | |
| dc.contributor.author | Sonesson, A. | |
| dc.contributor.author | Pina, Francisca | |
| dc.contributor.author | Forjaz-Lacera, João | |
| dc.contributor.author | Maia, Raquel | |
| dc.contributor.author | Kjollerstrom, Paula | |
| dc.contributor.author | Lavinha, João | |
| dc.contributor.author | Gonçalves, João | |
| dc.contributor.author | Faustino, Paula | |
| dc.date.accessioned | 2017-02-14T14:21:59Z | |
| dc.date.available | 2017-02-14T14:21:59Z | |
| dc.date.issued | 2016-11 | |
| dc.description.abstract | Hemoglobin (Hb) is a protein responsible for oxygen transportation from lungs to the entire body. It is composed by four globular subunits - the globins - each with a central core containing a heme molecule. Globins are encoded by the α- and β-globin gene clusters located at 16p13.3 and 11p15.5, respectively. The pattern of globin genes expression during development is precisely controlled by the interaction of cis-regulatory genomic regions (located in close proximity to and far from genes) with trans-activating/silencing factors within permissive chromatin domains. In fact, approximately 25-65 kb upstream of the α-globin genes there are four multispecies conserved sequences (MCS-R1 to R4) which are critical for the expression regulation of the downstream globin genes. The main objectives of this work were to characterize the molecular lesions underlying eight unusual cases of α-thalassemia or Hb H disease, and to understand their origin and functional consequences. Deletions were detected by Multiplex Ligation-dependent Probe Amplification (MLPA) using the SALSA MLPA P140B HBA kit (MCR-Holland). Additionally, specifically designed synthetic MLPA probes, as well as Gap-PCR and Sanger sequencing were performed for fine deletion breakpoint mapping. We have found seven different deletions (ranging from 3.3 to ≈323 kb), four of them not previously described. The four largest deletions removed all the α-globin genes, whereas the other three deletions removed one or more of the distal regulatory elements keeping the globin genes structurally intact. In one case, only the MCS-R2 (also known as HS-40) was removed and replaced by a 39 nt DNA fragment possibly resulting from a complex rearrangement that introduces new pieces of DNA (probably from Chrs. 3 and 7) bridging the two deletion breakpoints. In the remaining case, no deletion was found and the patient revealed to be a very unusual case of acquired alpha-thalassemia-myelodysplastic syndrome. It is important to detect individuals with this type of uncommon deletions as there is a 25% risk of having a child with Hb Bart’s hydrops fetalis or Hb H disease if their partner is a carrier of an α0-thal or α+-thal allele, respectively. Moreover, further investigation is currently being developed on one of these natural mutants which is bringing new insights into the long-range regulation mechanism of the globin gene expression and to the pathophysiology of the α-thalassemia. | pt_PT |
| dc.description.version | N/A | pt_PT |
| dc.identifier.uri | http://hdl.handle.net/10400.18/4165 | |
| dc.language.iso | eng | pt_PT |
| dc.peerreviewed | yes | pt_PT |
| dc.rights.uri | http://creativecommons.org/licenses/by-nc/4.0/ | pt_PT |
| dc.subject | Alpha-thalassaemia | pt_PT |
| dc.subject | Hemoglobinopatias | pt_PT |
| dc.subject | Doenças Genéticas | pt_PT |
| dc.subject | Deleção | pt_PT |
| dc.subject | MLPA | pt_PT |
| dc.title | Novel deletions and unusual genetic mechanisms underlying alpha-thalassemia | pt_PT |
| dc.type | conference object | |
| dspace.entity.type | Publication | |
| oaire.citation.conferencePlace | Coimbra, Portugal | pt_PT |
| oaire.citation.title | 20ª reunião anual da Sociedade Portuguesa de Genética Humana, 10-12 Novembro 2016 | pt_PT |
| rcaap.rights | openAccess | pt_PT |
| rcaap.type | conferenceObject | pt_PT |