| First Author | Huang S | Year | 2024 |
| Journal | Nat Commun | Volume | 15 |
| Issue | 1 | Pages | 7019 |
| PubMed ID | 39147774 | Mgi Jnum | J:353480 |
| Mgi Id | MGI:7713845 | Doi | 10.1038/s41467-024-50579-4 |
| Citation | Huang S, et al. (2024) Mutations in linker-2 of KLF1 impair expression of membrane transporters and cytoskeletal proteins causing hemolysis. Nat Commun 15(1):7019 |
| abstractText | The SP/KLF family of transcription factors harbour three C-terminal C2H2 zinc fingers interspersed by two linkers which confers DNA-binding to a 9-10 bp motif. Mutations in KLF1, the founding member of the family, are common. Missense mutations in linker two result in a mild phenotype. However, when co-inherited with loss-of-function mutations, they result in severe non-spherocytic hemolytic anemia. We generate a mouse model of this disease by crossing Klf1(+/-) mice with Klf1(H350R/+) mice that harbour a missense mutation in linker-2. Klf1(H350R/-) mice exhibit severe hemolysis without thalassemia. RNA-seq demonstrate loss of expression of genes encoding transmembrane and cytoskeletal proteins, but not globins. ChIP-seq show no change in DNA-binding specificity, but a global reduction in affinity, which is confirmed using recombinant proteins and in vitro binding assays. This study provides new insights into how linker mutations in zinc finger transcription factors result in different phenotypes to those caused by loss-of-function mutations. |
