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 (Klf3H275R). This change impaired binding of the mutant protein to KLF3's canonical DNA binding sequence. Heterozygous Klf3H275R 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 Klf3H275R 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.
Highlights
Congenital heart defects are the most common congenital malformations in humans affecting 1–2% of live births [1] and 18% of stillbirths [2]
To discover new causative genes important in cardiovascular development and function, we examined 1770 mice with randomly mutated genes and found a mutant with aortic valvular stenosis, and increased risk of fetal and neonatal death
Using linkage analysis and sequencing, we identified a protein-altering point mutation in the gene regulatory protein KLF3
Summary
Congenital heart defects are the most common congenital malformations in humans affecting 1–2% of live births [1] and 18% of stillbirths [2]. Causative mutations have been identified in families with inherited congenital heart defects [3] but in most cases remain unknown [2]. A strong genetic role is likely given high heritability scores, for example .0.7 for left-sided congenital heart defects [4,5,6]. To discover new genes important in cardiovascular development, we measured aortic blood velocity in an ultrasound screen undertaken to assess left ventricular outflow function, in the offspring of N-ethyl-N-nitrosourea (ENU) mutagenized male mice [7]. One mutant had very high aortic blood velocities due to aortic valvular stenosis and this trait was heritable. A dominant point mutation in the region encoding the DNA binding domain of Klf was found by linkage analysis and gene sequencing. KLF3 functions predominantly as a gene repressor [10] it has activator functions [11]
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