Mutational and clinical analysis of the ENG gene in patients with pulmonary arterial hypertension.
Pulmonary arterial hypertension (PAH) is a rare vascular disorder characterized by a capillary wedge pressure ≤ 15 mmHg and a mean pulmonary arterial pressure ≥ 25 mmHg at rest. PAH can be idiopathic, heritable or associated with other conditions. The aim of this study was to analyze the Endoglin (ENG) gene and assess the influence of the c.572G > A (p.G191D) mutation in patients with idiopathic or associated PAH. The correlation between the pathogenic mutations and clinical and functional parameters was further analyzed.



Sixteen different changes in the ENG gene were found in 44 out of 57 patients. After in silico analysis, we classified eight mutations as pathogenic in 16 of patients. The c.572G>A (p.G191D) variation was observed in ten patients, and the analysis for the splicing process using hybrid minigenes, with pSPL3 vector to assess splicing alterations, do not generate a new transcript. Age at diagnosis (p = 0.049) and the 6-min walking test (p = 0.041) exhibited statistically significant differences between carriers and non-carriers of pathogenic mutations. Patients with pathogenic mutations exhibited disease symptoms 8 years before non-carriers. Five patients with pathogenic mutations were carriers of another mutation in the BMPR2 or ACVRL1 genes.



We present a series of PAH patients with mutations in the ENG gene, some of them not previously described, exhibiting clinical and hemodynamic alterations suggesting that the presence of these mutations may be associated with the severity of the disease. Moreover, genetic analysis in patients with PAH may be of clinical relevance and indicates the complexity of the genetic background.
Department Biochemistry, Genetics and Immunology, Faculty of Biology, University of Vigo, As Lagoas Marcosende S/N, 36310, Vigo, Spain.|Instituto de Investigación Biomédica de Vigo (IBIV), Vigo, Spain.
Guillermo
G
Pousada
Complexo Hospitalario Universitario de Pontevedra, Servicio de neumología, Pontevedra, Spain.
Adolfo
A
Baloira
Department Biochemistry, Genetics and Immunology, Faculty of Biology, University of Vigo, As Lagoas Marcosende S/N, 36310, Vigo, Spain.
Diego
D
Fontán
Complexo Hospitalario Universitario de Pontevedra, Servicio de neumología, Pontevedra, Spain.
Marta
M
Núñez
Department Biochemistry, Genetics and Immunology, Faculty of Biology, University of Vigo, As Lagoas Marcosende S/N, 36310, Vigo, Spain. dianaval@uvigo.es.|Instituto de Investigación Biomédica de Vigo (IBIV), Vigo, Spain. dianaval@uvigo.es.
Diana
D
Valverde
D000328:Adult; D017668:Age of Onset; D004252:DNA Mutational Analysis / Q000379:methods*; D000071063:Endoglin / Q000235:genetics*; D005260:Female; D056726:Genetic Association Studies / Q000379:methods; D020022:Genetic Predisposition to Disease; D006801:Humans; D006976:Hypertension, Pulmonary / Q000235:genetics* / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D000070857:Walk Test; D055815:Young Adult
C064206:ENG protein, human; D000071063:Endoglin
ENG gene; Functional study; Genotype-phenotype correlation; Mutational analysis; Pulmonary arterial hypertension