05 February 2018 by Christina Eichstaedt

First identification of Krüppel-like factor 2 mutation in heritable pulmonary arterial hypertension

Background

Heritable pulmonary arterial hypertension (HPAH) is an autosomal dominantly inherited disease caused by mutations in the bone morphogenic protein receptor 2 gene and/or genes of its signalling pathway in about 85% of patients.

Objectives

Our main objective was to identify the genetic cause of the disease in this family using an next generation sequencing based PAH specific gene panel including all so far known PAH and further candidate genes.

Methods

We clinically and genetically analysed a HPAH family without mutations in previously described PAH genes. Clinical assessment included electrocardiogram, lung function, blood gas analysis, chest X-ray, laboratory testing, echocardiography and right heart catheterisation in case of suspected disease. Genetic diagnostics were performed using a PAH specific gene panel including all known 12 PAH genes and 20 further candidate genes by next-generation-sequencing.

Results

HPAH was invasively confirmed in two sisters and their father who died aged 32 years. No signs of HPAH were detected in five first degree family members. Both sisters were lung transplanted and remained stable during a follow-up of >20 years. We detected a novel missense mutation in the Krüppel-like factor 2 (KLF2) likely leading to a disruption of gene function. The same KLF2 mutation has been described as a recurrent somatic mutation in B-cell lymphoma. Neither the healthy family members carried the mutation nor >120,000 controls.
Conclusions: These findings point to KLF2 as a new PAH gene. Further studies are needed to assess frequency and implication of KLF2 mutations in PAH patients.

About the author


profile picture of Christina Eichstaedt

Christina Eichstaedt

Post-Doc

Thoraxclinic at the University Hospital Heidelberg and Institute of Human Genetics, Heiderlberg University

Germany

Key Contributors

Christina A. Eichstaedt, PhD1,2,3*, Jie Song, MD1,2,3, Rebecca Rodríguez Viales, PhD4, Zixuan Pan, MD1,3, Nicola Benjamin, MSc1,3,Christine Fischer, Dr sc hum2, Marius M. Hoeper, MD5, Silvia Ulrich, MD6; Katrin Hinderhofer, PhD2 and Ekkehard Grünig, MD1,3 1 Centre for Pulmonary Hypertension, Thoraxclinic at the University Hospital Heidelberg, Röntgenstrasse 1, 69126 Heidelberg, Germany 2 Institute of Human Genetics, Heidelberg University, Im Neuenheimer Feld 366, 69120 Heidelberg, Germany 3 Translational Lung Research Centre Heidelberg (TLRC), German Centre for Lung Research (DZL), Heidelberg, Germany 4 European Molecular Biology Laboratory, Meyerhofstrasse 1, 69117 Heidelberg, Germany 5 Hannover Medical School, Clinic for Pneumology, Carl-Neuberg Str 1, 30623 Hannover and German Centre for Lung Research (DZL), Hannover, Germany 6 Clinic of Pulmonology, University Hospital Zurich, Rämistrasse 100, 8091 Zürich, Switzerland


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