A new gene for heritable pulmonary arterial hypertension: Krüppel-like factor 2
23 February 2017 (online)
Heritable pulmonary arterial hypertension (HPAH) is an autosomal dominantly inherited disease caused by mutations in the bone morphogenic protein receptor 2 (BMPR2) gene and/or genes of its signalling pathway in about 80% of patients. This study was performed in a HPAH family without mutations in previously described PAH genes to identify further disease-causing genes.
Method and Results:
In all family members, clinical assessment and genetic analysis were performed. Clinical assessment included electrocardiogram, lung function, chest X-ray, laboratory testing, echocardiography at rest and during exercise, 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. Potential mutations were confirmed with Sanger sequencing.
HPAH was invasively confirmed in two sisters aged 25 and their affected father who died aged 32 years. No signs of HPAH were detected in five first degree family members. The two sisters were successfully 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, c.862C>T p.H288Y) likely leading to a loss of function. Neither the healthy family members carried the mutation nor > 60,000 individuals in a control database.
These findings identify KLF2 as a new PAH gene. The identified germline KLF2 mutation has previously been described as somatic loss-of-function mutation in B-cell lymphoma, which may strengthen the potential links between PAH and neoplasm and help understanding the pathogenesis of the disease.