KLF1-null neonates display hydrops fetalis and a deranged erythroid transcriptome.
We describe a case of severe neonatal anemia with kernicterus caused by compound heterozygosity for null mutations in KLF1, each inherited from asymptomatic parents. One of the mutations is novel. This is the first described case of a KLF1-null human. The phenotype of severe nonspherocytic hemolytic anemia, jaundice, hepatosplenomegaly, and marked erythroblastosis is more severe than that present in congenital dyserythropoietic anemia type IV as a result of dominant mutations in the second zinc-finger of KLF1. There was a very high level of HbF expression into childhood (>70%), consistent with a key role for KLF1 in human hemoglobin switching. We performed RNA-seq on circulating erythroblasts and found that human KLF1 acts like mouse Klf1 to coordinate expression of many genes required to build a red cell including those encoding globins, cytoskeletal components, AHSP, heme synthesis enzymes, cell-cycle regulators, and blood group antigens. We identify novel KLF1 target genes including KIF23 and KIF11 which are required for proper cytokinesis. We also identify new roles for KLF1 in autophagy, global transcriptional control, and RNA splicing. We suggest loss of KLF1 should be considered in otherwise unexplained cases of severe neonatal NSHA or hydrops fetalis.
Mater Research Institute, Faculty of Medicine and Biomedical Sciences, The University of Queensland, Woolloongabba, QLD, Australia;
Graham W
GW
Magor
Mater Research Institute, Faculty of Medicine and Biomedical Sciences, The University of Queensland, Woolloongabba, QLD, Australia; School of Medicine, Faculty of Medicine and Biomedical Sciences, The University of Queensland, St Lucia, QLD, Australia;
Michael R
MR
Tallack
Mater Research Institute, Faculty of Medicine and Biomedical Sciences, The University of Queensland, Woolloongabba, QLD, Australia;
Kevin R
KR
Gillinder
Mater Research Institute, Faculty of Medicine and Biomedical Sciences, The University of Queensland, Woolloongabba, QLD, Australia;
Charles C
CC
Bell
Queensland Pathology, Brisbane, QLD, Australia;
Naomi
N
McCallum
Department of Hematology, Royal Brisbane and Women's Hospital, Brisbane, QLD, Australia; and.
Bronwyn
B
Williams
Mater Research Institute, Faculty of Medicine and Biomedical Sciences, The University of Queensland, Woolloongabba, QLD, Australia; Department of Cancer Services, Princess Alexandra Hospital, Brisbane, QLD, Australia.
Andrew C
AC
Perkins
D000751:Anemia, Neonatal / Q000097:blood / Q000150:complications / Q000235:genetics* / Q000473:pathology*; D001343:Autophagy; D004900:Erythroblasts / Q000378:metabolism / Q000473:pathology; D004920:Erythropoiesis; D005260:Female; D017353:Gene Deletion; D005786:Gene Expression Regulation; D006801:Humans; D015160:Hydrops Fetalis / Q000097:blood / Q000235:genetics* / Q000473:pathology*; D007231:Infant, Newborn; D051741:Kruppel-Like Transcription Factors / Q000235:genetics* / Q000378:metabolism; D008297:Male; D059467:Transcriptome
D051741:Kruppel-Like Transcription Factors; C080774:erythroid Kruppel-like factor