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Titolo: HPFH From Klf1 Haploinsufficiency Combined to Transcriptional Heterozygous β-Thalassemia
Autori: 
Data di pubblicazione: 2011
Rivista: 
BLOOD  
Citazione: HPFH From Klf1 Haploinsufficiency Combined to Transcriptional Heterozygous β-Thalassemia / Paolo Moi; Giuseppina M. Marini; Isadora Asunis; Loredana Porcu; Cabriolu A; Stefania Satta; Luciana Perseu; Liliana Maccioni; Antonio Cao and Renzo Galanello. - In: BLOOD. - ISSN 0006-4971. - (2011). ((Intervento presentato al convegno ASH 2011 tenutosi a SAN DIEGO nel 10-13 DIC 2012.
Abstract: KLF1 mutations are emerging as a frequent cause of hereditary persistence of hemoglobin F (HPFH). Although it has been initially proposed that KLF1 haplo-insufficiency could determine KLF1 related HPFH, following studies have shown that isolated mono allelic Klf1 defects do not or only occasionally raise HbF and that biallelic KLF1 mutations are needed for HPFH to fully develop. Here we present a different mechanism of HPFH in a Sardinian family with a rare genetic combination in which HPFH with HbF levels up to 20% is caused by Klf1 haploinsufficiency combined to a β-thalassemia transcriptional defect from a – 87C to G mutation in the proximal CACCC box, the canonical Klf1 binding site. Other known determinants of HPFH in the Myb, -globin or Bcl11 gene or variation in the expression of Bcl11 could not account for the increased HbF expression in the compound heterozygotes compared to the simple KLF1 or βThal-87 heterozygotes siblings. Hence, in this family delayed hemoglobin switching and HPFH are not dependent upon the absolute reduction in the free Klf1 concentration, as suggested by current models, but from the reduction in the amount of CACCC bound Klf1. This observation suggests that CACCC bound Klf1 is the primary anchor site for the LCR and that Klf1 mediated bridging between LCR and β-globin promoter is the most important determinant for hemoglobin switching in humans.
Handle: http://hdl.handle.net/11584/87948
Tipologia:4.1 Contributo in Atti di convegno

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