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Novel large deletions in the human alpha-globin gene cluster: Clarifying the HS-40 long-range regulatory role in the native chromosome environment
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Orientador(es)
Resumo(s)
Globin genes, which encode the protein subunits of hemoglobin (Hb), are organized in two different gene
clusters and present a coordinated and differential pattern of expression during development. Concerning
the human α-globin gene cluster (located at chromosome region 16p13.3), four upstream highly conserved
elements known as multispecies conserved sequences (MCS-R1-4) or DNase I hypersensitive sites (HSs) are
implicated in the long-range regulation of downstream gene expression. However, only the absence of the
MCS-R2 site (HS-40) has proven to drastically downregulate the expression of those genes, and
consequently, it has been regarded as the major and crucial distal regulatory element.
In this study, Multiplex Ligation-dependent Probe Amplification was used to screen for deletions in the
telomeric region of the short arm of chromosome 16, in an attempt to explain the α-thalassemia or the HbH
disease present in a group of Portuguese patients. We report four novel and five uncommon deletions that
remove the α-globin distal regulatory elements and/or the complete α-globin gene cluster. Interestingly, one
of them occurred de novo and removes all HSs except HS-10, while other eliminates only the HS-40 site, the
latter being replaced by the insertion of a 39 nucleotide orphan sequence.
Our results demonstrate that HS-10 alone does not significantly enhance the α-globin gene expression. The
absence of HS-40 in homozygosity, found in a patient with Hb H disease, strongly downregulates the
expression of α-globin genes but it is not associated with a complete absence of α-globin chain production.
The study of naturally occurring deletions in this region is of great interest to understand the role of each
upstream regulatory element in the native human erythroid environment.
Descrição
Palavras-chave
α-thalassemia HbH Large deletion α-globin gene cluster HS-40 Doenças Genéticas Patologias do Glóbulo Vermelho
Contexto Educativo
Citação
Blood Cells Mol Dis. 2010 Aug 15;45(2):147-53. Epub 2010 Jun 30
Editora
Elsevier