User:Zoonose1/sandbox

Function
Studies in mice first demonstrated the critical function of KLF1 in hematopoietic development. KLF1 deficient (knockout) mouse embryos exhibit a lethal anemic phenotype, fail to promote the transcription of adult β-globin, and die by embryonic day 15. Over-expression of KLF1 results in a reduction of the number of circulating platelets and hastens the onset of the β-globin gene.

KLF1 coordinates the regulation of six cellular pathways that are all essential to terminal erythroid differentiation:


 * 1) Cell Membrane & Cytoskeleton
 * 2) Apoptosis
 * 3) Heme Synthesis & Transport
 * 4) Cell Cycling
 * 5) Iron Procurement
 * 6) Globin Chain Production

It has also been linked to three main processes that are all essential to transcription of the β globin gene: KLF1 binds specifically to the "CACCC" motif of the β-globin gene promoter. When natural mutations occur in the promoter, β+ thalassemia can arise in humans. Thalassemia's prevalence (2 million worldwide carry the trait) makes KLF1 clinically significant.
 * 1) Chromatin remodeling
 * 2) Modulation of the gamma to beta globin switch
 * 3) Transcriptional activation

Clinical significance
Next-Generation sequencing efforts have revealed a surprisingly high prevalence of mutations in human KLF1. The chance of a KLF1 null child being conceived is approximately 1:24,000 in Southern China. With pre-natal blood transfusions and bone marrow transplant, it is possible to be born without KLF1. Most mutations in KLF1 lead to a recessive loss-of-function phenotype, however semi-dominant mutations have been identified in humans and mice as the cause of a rare inherited anemia CDA type IV.

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