High frequency of ENG and ALK1/ACVRL1 mutations in German HHT patients

Abstract

Morbus Osler or HHT (hereditary hemorrhagic telangiectasia) is a disorder of the fibrovascular tissue that is inherited in an autosomal dominant way with frequency rates between 1:2,500 and 1:40,000. The disease provokes malformations of the blood vessels sometimes resulting in life-threatening complications. Presently, two genes involved in the development of HHT have been identified: ACVRL1 and ENG. Both of them encode proteins that belong to the TGF-beta receptor complex family and play an essential role in the formation of the vascular system. Recently, several mutations in ACVRL1 and ENG have been described in other European populations. However, no data concerning mutation frequencies in the German population have been reported so far. Therefore, we screened our collective of German HHT patients (28 single cases and 11 familial cases) for mutations in both genes by direct sequencing. We detected 11 mutations already described elsewhere and 19 novel ones. Furthermore, evidence for the pathogenic role of four new missense mutations was collected by screening a healthy control collective using RFLP analysis. Interestingly, the majority of ACVRL1 mutations represented missense mutations, whereas mutations in ENG mostly resulted in a shortened protein. Our results demonstrate the importance of ACVRL1 and ENG mutations in German HHT patients displaying mutation frequencies over 80%.