KLF2 was first reported in relation to Pulmonary Arterial Hypertension in 2017 (Eichstaedt et al., PMID: 28188237). Pulmonary Arterial Hypertension is a group of diseases characterized by elevated pulmonary arterial resistance leading to right heart failure. Summary of Genetic Evidence: One missense variant has been reported in one proband and her affected sister (PMID: 28188237). The mechanism of pathogenicity appears to be loss of function. Summary of Experimental Evidence: This gene-disease association is supported by expression studies, protein interaction studies, biochemical function studies, and studies analyzing functional alteration in patient cells (PMID: 7565748, PMID: 10458913, PMID: 15136591, PMID: 32132543). The first expression study (PMID: 7565748 and PMID: 10458913), showed KLF2 expressed in both the mouse and a human lung. The next paper (PMID: 15136591), included both a biochemical function experiment and a protein interaction experiment. The biochemical function experiment demonstrated that overexpression of p300 was able to rescue KLF2-mediated inhibition of the NF-B concatemer and augmented KLF2 induction of the eNOS promoter. The protein interaction experiment demonstrated that KLF2 induction of the eNOS promoter is dependent on DNA binding. The next paper included analysis of functional alteration in patient cells (PMID: 32132543). The functional alteration experiment demonstrated that HPAH patients with c-terminal (p.H288Y) KLF2 mutation showed a marked up-regulation of Notch4 and ETS-1 in the remodeled pulmonary vasculature, identified by endothelial vWF and a prominent α-SMA staining in the small, normally non-muscularized arterioles. Although we do have 3 points from the experimental evidence category, the maximum points allowed in the functional category (2) has been reached, and this category will therfore receive 2.5 points, as shown in the classifcation summary. In summary, KLF2’s association with autosomal dominant pulmonary arterial hypertension is limited. The classification was approved by the PH GCEP on 8/30/2022 (SOP Version 9).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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