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Identification of a low frequency missense mutation in MUC6 contributing to pulmonary artery hypertension by whole-exome sequencing.

ABSTRACT: Pulmonary arterial hypertension (PAH) represents a progressive disease characterized by abnormally high blood pressure in the pulmonary artery. Although mutations in the bone morphogenetic receptor 2 (BMPR2) are found in 80% of heritable, their low penetrance suggests that other unidentified genetic modifiers are required for this disease. In this report, whole-exome sequencing (WES) and a linkage analysis were performed on genomic DNA isolated from four affected relatives and one non-affected relative in two PAH families. By focusing on meaningful variants which were presented in the four affected family members, but not presented in the non-affected individual, 49 SNP and eight indel variants in 39 genes were identified as candidates. Further high-throughput multiplex genotyping and Sanger sequencing were carried out to confirm the putative causal mutations in 150 individuals (30 idiopathic PAH [IPAH] patients, 30 chronic thromboembolic pulmonary hypertension [CTEPH] patients, and 90 normal controls). A heterozygous and deleterious mutation in the gene MUC6 (p.Pro1716Ser) was confirmed in the IPAH group (20/30, 67%) and CTEPH group (1/30, 3.33%); no variant was detected in the 90 normal controls. MUC6, which is short for mucin 6, encodes high molecular weight glycoprotein produced by many epithelial tissues and forms an insoluble mucous barrier that protects the lumens. We re-confirmed this low frequency mutation with the 1000 Genomes database across all species; no population or frequency data of this allele were acquired. We also found that this mutation site was highly conserved in different species and predicted MUC6 has the protection function of the airway and pneumoangiogram based on genomic sequence data. The compound heterozygous MUC6 gene mutation (p.Pro1716Ser) suggests a novel disease mechanism leading to PAH.

SUBMITTER: Zou L

PROVIDER: S-EPMC6104216 | biostudies-literature | 2018 Jul-Sep

REPOSITORIES: biostudies-literature

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Identification of a low frequency missense mutation in MUC6 contributing to pulmonary artery hypertension by whole-exome sequencing.

Zou Lihui L Li Wenqing W Han Jingli J Yang Yuanhua Y Jin Junhua J Xiao Fei F Xu Xiaomao X Zhai Zhenguo Z

Pulmonary circulation 20180726 3

Pulmonary arterial hypertension (PAH) represents a progressive disease characterized by abnormally high blood pressure in the pulmonary artery. Although mutations in the bone morphogenetic receptor 2 (BMPR2) are found in 80% of heritable, their low penetrance suggests that other unidentified genetic modifiers are required for this disease. In this report, whole-exome sequencing (WES) and a linkage analysis were performed on genomic DNA isolated from four affected relatives and one non-affected r ...[more]

PMID: 30047301

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Project description:BackgroundGenetic variants could be identified in subjects with idiopathic and heritable pulmonary arterial hypertension (PAH). The 6th World Symposium on Pulmonary Hypertension (WSPH) provided a list of genes with evidence of association with PAH. However, reports using whole exome sequencing (WES) from southeastern Asian PAH cohorts were scarce.MethodsSubjects with idiopathic and heritable PAH (N = 45) from two medical centers in central Taiwan were screened for PAH related gene variants. The genomic DNA was prepared from peripheral blood lymphocytes. We performed WES for all patients enrolled in this study. All identified gene variants were validated by polymerase-chain reaction and Sanger sequencing. The clinical and hemodynamic data were compared between bone morphogenetic protein receptor type-2 (BMPR2) gene variants carriers vs. non-carriers.ResultsEight patients (8/45 = 17.8%) was identified carrying BMPR2 gene variants and 8 patients (8/45 = 17.8%) had other WSPH-listed PAH-related gene variants (1 with ACVRL1, 1 with ENG, 1 with SMAD9, 1 with SMAD1, 1 with ATP13A3 and 3 with AQP1). In addition, a total of 14 non-WSPH-listed PAH-related genetic variant sites (ABCC8, NOTCH1, NOTCH2, NOTCH3, JAG1, BMP10, GGCX, FBLN2, ABCA3 and PTGIS) were found in this PAH cohort. Subjects carrying BMPR2 gene variant (N = 8) were younger at diagnosis of PAH (30 ± 11 vs 49 ± 13 years, p = 0.001) than the non-carrier group (N = 37). BMPR2 variant carriers had a trend toward having higher mean pulmonary arterial pressure (PAP) (61 ± 19 vs. 51 ± 13 mmHg, p = 0.076) than the non-carriers upon initial diagnosis. Pulmonary vascular resistance, right atrial pressure, cardiac output, as well as functional class were similar between BMPR2 variant carriers and non-carriers at initial diagnosis.ConclusionsWe identified 17.8% of patients with BMPR2 gene variants and 17.8% subjects with other 6th WSPH-listed PAH-related gene variants in a Taiwanese idiopathic and heritable PAH cohort. PAH patients carrying BMPR2 variants presented at a younger age with a trend toward having higher mean PAP at initial diagnosis.

Dataset Information

Identification of a low frequency missense mutation in MUC6 contributing to pulmonary artery hypertension by whole-exome sequencing.

Publications

Identification of a low frequency missense mutation in MUC6 contributing to pulmonary artery hypertension by whole-exome sequencing.

Similar Datasets

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