Mutations in RASA1 and GDF2 identified in patients with clinical features of hereditary hemorrhagic telangiectasia

Abstract

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant vascular disorder caused by mutations in ENG, ACVRL1 and SMAD4, which function in regulating the transforming growth factor beta and bone morphogenetic protein signaling pathways. Symptoms of HHT can be present in individuals who test negative for mutations in these three genes indicating other genes may be involved. In this study, we tested for mutations in two genes, RASA1 and GDF2, which were recently reported to be involved in vascular disorders. To determine whether RASA1 and GDF2 have phenotypic overlap with HHT and should be included in diagnostic testing, we developed a next-generation sequencing assay to detect mutations in 93 unrelated individuals who previously tested negative for mutations in ENG, ACVRL1 and SMAD4, but were clinically suspected to have HHT. Pathogenic mutations in RASA1 were identified in two samples (2.15%) and a variant of unknown significance in GDF2 was detected in one sample. All three individuals experienced epistaxis with dermal lesions described in medical records as telangiectases. These results indicate that the inclusion of RASA1 and GDF2 screening in individuals suspected to have HHT will increase the detection rate and aid clinicians in making an accurate diagnosis.

A heterodimer formed by bone morphogenetic protein 9 (BMP9) and BMP10 provides most BMP biological activity in plasma

“…The single substitution of Lys 317 to Gln 317 did not impair BMP9 maturation (Fig. S2), thus indicating that HHT disease in this patient is not linked to a BMP9 processing defect as it had been suggested (27). The double mutant RQAR was only partially processed but could be completely cleaved when furin was overexpressed, whereas the triple mutant RQAA was not cleaved at all even in the presence of overexpressed furin (Fig.…”

“…The BMP9 furin-cleavage site 316 RKKR was mutated to 316 RQKR, 316 RQAR 319 , or 316 RQAA 319 . The first mutant was generated to mimic a substitution mutation identified in a patient suffering from HHT (27). The two others replaced basic amino acids by alanine residues to avoid furin cleavage.…”

Characterization of GDF2 Mutations and Levels of BMP9 and BMP10 in Pulmonary Arterial Hypertension

“…Heterozygous GDF2 mutations have been identified previously in a small number of patients with a vascular anomaly syndrome resembling hereditary hemorrhagic telangiectasia (HHT) (26,27). The mutations in HHT patients were distinct from those reported in PAH but were also predicted to lead to altered cellular processing.…”

Expanding the clinical and molecular findings in RASA1 capillary malformation-arteriovenous malformation

“…Recently, lymphatic manifestations such as lymphedema and chylothorax were described as part of the phenotypic spectrum of RASA1-related disorders [10]. RASA1 variants have additionally been reported in individuals clinically suspected to have hereditary hemorrhagic telangiectasia (HHT) who had epistaxis and dermal lesions described as telangiectases [11].…”