title: ENU-induced mutation in the DNA-binding domain of KLF3 reveals important roles for KLF3 in cardiovascular development and function in mice.
abstract: KLF3 is a Krüppel family zinc finger transcription factor with widespread tissue expression and no previously known role in heart development. In a screen for dominant mutations affecting cardiovascular function in N-ethyl-N-nitrosourea (ENU) mutagenized mice, we identified a missense mutation in the Klf3 gene that caused aortic valvular stenosis and partially penetrant perinatal lethality in heterozygotes. All homozygotes died as embryos. In the first of three zinc fingers, a point mutation changed a highly conserved histidine at amino acid 275 to arginine (Klf3(H275R) ). This change impaired binding of the mutant protein to KLF3's canonical DNA binding sequence. Heterozygous Klf3(H275R) mutants that died as neonates had marked biventricular cardiac hypertrophy with diminished cardiac chambers. Adult survivors exhibited hypotension, cardiac hypertrophy with enlarged cardiac chambers, and aortic valvular stenosis. A dominant negative effect on protein function was inferred by the similarity in phenotype between heterozygous Klf3(H275R) mutants and homozygous Klf3 null mice. However, the existence of divergent traits suggested the involvement of additional interactions. We conclude that KLF3 plays diverse and important roles in cardiovascular development and function in mice, and that amino acid 275 is critical for normal KLF3 protein function. Future exploration of the KLF3 pathway provides a new avenue for investigating causative factors contributing to cardiovascular disorders in humans.
authors.affiliation: Samuel Lunenfeld Research Institute of Mount Sinai Hospital, Toronto, Ontario, Canada.
authors.forename: Lois
authors.initials: L
authors.lastname: Kelsey
authors.forename: Ann M
authors.initials: AM
authors.lastname: Flenniken
authors.forename: Dawei
authors.initials: D
authors.lastname: Qu
authors.forename: Alister P W
authors.initials: AP
authors.lastname: Funnell
authors.forename: Richard
authors.initials: R
authors.lastname: Pearson
authors.forename: Yu-Qing
authors.initials: YQ
authors.lastname: Zhou
authors.forename: Irina
authors.initials: I
authors.lastname: Voronina
authors.forename: Zorana
authors.initials: Z
authors.lastname: Berberovic
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Wood
authors.forename: Susan
authors.initials: S
authors.lastname: Newbigging
authors.forename: Edward S
authors.initials: ES
authors.lastname: Weiss
authors.forename: Michael
authors.initials: M
authors.lastname: Wong
authors.forename: Ivan
authors.initials: I
authors.lastname: Quach
authors.forename: S Y Sandy
authors.initials: SY
authors.lastname: Yeh
authors.forename: Ashish R
authors.initials: AR
authors.lastname: Deshwar
authors.forename: Ian C
authors.initials: IC
authors.lastname: Scott
authors.forename: Colin
authors.initials: C
authors.lastname: McKerlie
authors.forename: Mark
authors.initials: M
authors.lastname: Henkelman
authors.forename: Peter
authors.initials: P
authors.lastname: Backx
authors.forename: Jeremy
authors.initials: J
authors.lastname: Simpson
authors.forename: Lucy
authors.initials: L
authors.lastname: Osborne
authors.forename: Janet
authors.initials: J
authors.lastname: Rossant
authors.forename: Merlin
authors.initials: M
authors.lastname: Crossley
authors.forename: Benoit
authors.initials: B
authors.lastname: Bruneau
authors.forename: S Lee
authors.initials: SL
authors.lastname: Adamson
mesh_terms: D000818:Animals; D001024:Aortic Valve Stenosis / Q000235:genetics* / Q000503:physiopathology; D002318:Cardiovascular Diseases / Q000235:genetics* / Q000503:physiopathology; D004268:DNA-Binding Proteins; D005038:Ethylnitrosourea / Q000737:chemistry; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D020125:Mutation, Missense; D059372:Nucleotide Motifs / Q000235:genetics
chemical_list: D004268:DNA-Binding Proteins; C501168:KLF3 protein, human; D051741:Kruppel-Like Transcription Factors; D005038:Ethylnitrosourea