2 gene, and four of them showed two mutations in this gene.

2 gene, and four of them showed two mutations in this gene. All these changes were predicted to alter the splicing process or the conservation of the protein, producing a shorter transcript or a misfolding protein susceptible of degradation, which could prevent achieving a minimum protein translation and therefore, the development of the disease29,37. Two of these patients were carriers of a third mutation, previously described, in ENG gene. These mutations are located in the first exons and were predicted to affect the splicing process. Thus, mutations in ENG gene could prevent the correct anchoring of ENG protein in the cell membrane, impairing TGF-/ALK1 signalling responses33. On the other hand, eight patients were double heterozygotes for BMPR2 and ENG mutations (one of them showed a third mutation in ACVRL1 gene), one patient had two mutations in ENG gene and the remaining patients showed different combination of mutated genes: one patient was double heterozygote for ENG and ACVRL1, another two for BMPR2 and ACVRL1genes and finally, one patient showed a combination of ACVRL1 with KCNA5 genes. In the last years a second hit hypothesis have been proposed that two mutations, one major and other as modulator, in the same gene or different gene take place32,33. It has been order EPZ004777 described that after BMPR2, ACVRL1 is the gene most frequently mutated in PAH patients. However, we show that ENG was the second gene most frequent in our cohort. All of these genes have been described to be involved in the development of the disease with or Necrosulfonamide site without HHT, being BMPR2 the major causal gene and the others genetic modifiers modulating the penetrance of the disease32,36,38. Although almost all mutations described in BMPR2 gene have been established as pathogenic, others remains indeterminate, as mutations in the cytoplasmic tail that still retain capacity for downstream signalling. The pathogenic impact of others genes in the disruption of the TGF- pathway directly or by modulating related pathways, is still unknown39?2. None of our patients had relatives with PAH, so we could not perform segregation analysis; but none of the mutations described here were detected in 110 control chromosomes. As most of the mutations identified in PAH are private, and due to the confluence of two or more mutations in several genes, performing genotype-phenotypeScientific RepoRts | 6:33570 | DOI: 10.1038/srepwww.nature.com/scientificreports/Patients with several pathogenic Patients with several pathogenic mutations vs patients with single mutation mutations vs patients without mutation Clinical data 15 4 M/11 F 46 ?17 48 ?15 72 ?17 10.9 ?1.7 1.7 ?0.5 389 ?163 7 IPAH/8 APAH 10 p-value — 0.045 0.035 0.239 0.542 0.030 0.035 0.075 0.401 0.011 p-value — 0.040 0.030 0.368 0.422 0.025 0.018 0.027 0.472 0.Clinical features and hemodynamic parameters Number Gender Age at diagnosis (years) mPaP (mmHg) sPaP (mmHg) PVR (mmHg.l-1.m-1) CI (l.min-1.m-2) 6MWT (m) PAH types No response to treatmentTable 5. Clinical and p-values for genotype-phenotype correlation comparing patients with several mutations vs patients with one pathogenic mutations. Values are expressed as mean ?standard deviation; F: female, M: male; mPaP: mean pulmonary artery pressure; sPaP: systolic pulmonary artery pressure; PVR: pulmonary vascular resistence; CI: cardiac index; 6MWT: 6 minute walking test; IPAH: idiopathic pulmonary arterial hypertension; APAH: associated pulmonary arterial hypertension. correlations rev.2 gene, and four of them showed two mutations in this gene. All these changes were predicted to alter the splicing process or the conservation of the protein, producing a shorter transcript or a misfolding protein susceptible of degradation, which could prevent achieving a minimum protein translation and therefore, the development of the disease29,37. Two of these patients were carriers of a third mutation, previously described, in ENG gene. These mutations are located in the first exons and were predicted to affect the splicing process. Thus, mutations in ENG gene could prevent the correct anchoring of ENG protein in the cell membrane, impairing TGF-/ALK1 signalling responses33. On the other hand, eight patients were double heterozygotes for BMPR2 and ENG mutations (one of them showed a third mutation in ACVRL1 gene), one patient had two mutations in ENG gene and the remaining patients showed different combination of mutated genes: one patient was double heterozygote for ENG and ACVRL1, another two for BMPR2 and ACVRL1genes and finally, one patient showed a combination of ACVRL1 with KCNA5 genes. In the last years a second hit hypothesis have been proposed that two mutations, one major and other as modulator, in the same gene or different gene take place32,33. It has been described that after BMPR2, ACVRL1 is the gene most frequently mutated in PAH patients. However, we show that ENG was the second gene most frequent in our cohort. All of these genes have been described to be involved in the development of the disease with or without HHT, being BMPR2 the major causal gene and the others genetic modifiers modulating the penetrance of the disease32,36,38. Although almost all mutations described in BMPR2 gene have been established as pathogenic, others remains indeterminate, as mutations in the cytoplasmic tail that still retain capacity for downstream signalling. The pathogenic impact of others genes in the disruption of the TGF- pathway directly or by modulating related pathways, is still unknown39?2. None of our patients had relatives with PAH, so we could not perform segregation analysis; but none of the mutations described here were detected in 110 control chromosomes. As most of the mutations identified in PAH are private, and due to the confluence of two or more mutations in several genes, performing genotype-phenotypeScientific RepoRts | 6:33570 | DOI: 10.1038/srepwww.nature.com/scientificreports/Patients with several pathogenic Patients with several pathogenic mutations vs patients with single mutation mutations vs patients without mutation Clinical data 15 4 M/11 F 46 ?17 48 ?15 72 ?17 10.9 ?1.7 1.7 ?0.5 389 ?163 7 IPAH/8 APAH 10 p-value — 0.045 0.035 0.239 0.542 0.030 0.035 0.075 0.401 0.011 p-value — 0.040 0.030 0.368 0.422 0.025 0.018 0.027 0.472 0.Clinical features and hemodynamic parameters Number Gender Age at diagnosis (years) mPaP (mmHg) sPaP (mmHg) PVR (mmHg.l-1.m-1) CI (l.min-1.m-2) 6MWT (m) PAH types No response to treatmentTable 5. Clinical and p-values for genotype-phenotype correlation comparing patients with several mutations vs patients with one pathogenic mutations. Values are expressed as mean ?standard deviation; F: female, M: male; mPaP: mean pulmonary artery pressure; sPaP: systolic pulmonary artery pressure; PVR: pulmonary vascular resistence; CI: cardiac index; 6MWT: 6 minute walking test; IPAH: idiopathic pulmonary arterial hypertension; APAH: associated pulmonary arterial hypertension. correlations rev.

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