<i>SOX17</i> Mutations in Japanese Patients with Pulmonary Arterial Hypertension

Hiraide, Takahiro; Kataoka, Masaharu; Suzuki, Hisato; Aimi, Yuki; Chiba, Tomohiro; Kanekura, Kohsuke; Satoh, Tsuyoshi; Fukuda, Keiichi; Gamou, Shinobu; Kosaki, Kenjiro

doi:10.1164/rccm.201804-0766le

Cited by 26 publications

(23 citation statements)

References 10 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Likely pathogenic variants were detected in 0.7% of patients with IPAH and 3.2% of patients with PAH-associated congenital heart disease, with the vast majority clustered within the high mobility group box. A similar study in a cohort of Japanese patients with HPAH or IPAH identified three additional SOX17 variants 79 . Of interest, gene-based, case-control analyses also revealed an over-representation of rare deleterious variations in a number of putative SOX17 target genes, indicating a key role for this pathway in PAH aetiology 78 .…”

Section: [H2] Functional Effect Of Novel Gene Defectsmentioning

confidence: 66%

Molecular genetic framework underlying pulmonary arterial hypertension

et al. 2019

View full text Add to dashboard Cite

| Pulmonary arterial hypertension (PAH) is a rare, progressive disorder typified by occlusion of the pulmonary arterioles owing to endothelial dysfunction and uncontrolled proliferation of pulmonary artery smooth muscle cells and fibroblasts. Vascular occlusion can lead to increased pressure in the pulmonary arteries, often resulting in right ventricular failure with shortness of breath and syncope. Since the identification of BMPR2, which encodes a receptor in the transforming growth factor-β superfamily, the development of highthroughput sequencing approaches to identify novel causal genes has substantially advanced our understanding of the molecular genetics of PAH. In the past 6 years, additional pathways involved in PAH susceptibility have been described through the identification of deleterious genetic variants in potassium channels (KCNK3 and ABCC8) and transcription factors (TBX4 and SOX17), among others. Although familial PAH most often has an autosomal dominant pattern of inheritance, cases of incomplete penetrance and evidence of genetic heterogeneity support a model of PAH as a Mendelian disorder with complex disease features. In this Review, we outline the latest advances in the detection of rare and common genetic variants underlying PAH susceptibility and disease progression. These findings have clinical implications on lung vascular function and can help to identify mechanistic pathways amenable to pharmacological intervention. P ag e | 2

show abstract

Section: [H2] Functional Effect Of Novel Gene Defectsmentioning

confidence: 66%

Molecular genetic framework underlying pulmonary arterial hypertension

et al. 2019

View full text Add to dashboard Cite

show abstract

“…A recurrent frameshift variant, p.(Leu167Trpfs*213), was identified in three APAH-CHD cases with age-of-onset ranging from 7 months to 5 years. We [ 11 , 22 ] and others [ 41 , 42 ] have identified SOX17 variants in IPAH cases but with lower frequency in adults. Combined data from five cohorts ([ 11 , 13 , 22 , 41 , 42 ] indicate that SOX17 variants contribute to 7% of all pediatric-onset PAH cases compared to 0.4% of adult-onset cases ( Figure 3 ).…”

Section: Genetics Of Pediatric Pah—current Knowledgementioning

confidence: 99%

“…We [ 11 , 22 ] and others [ 41 , 42 ] have identified SOX17 variants in IPAH cases but with lower frequency in adults. Combined data from five cohorts ([ 11 , 13 , 22 , 41 , 42 ] indicate that SOX17 variants contribute to 7% of all pediatric-onset PAH cases compared to 0.4% of adult-onset cases ( Figure 3 ). Protein modeling indicates that at least three of the APAH-CHD case missense variants localize to the transcription factor DNA binding pocket [ 22 ], and missense variants in this region have been shown to impair both direct DNA binding and SOX17/β-catenin nucleoprotein complexes at target gene promoters [ 43 , 44 ].…”

Section: Genetics Of Pediatric Pah—current Knowledgementioning

confidence: 99%

Genetics and Genomics of Pediatric Pulmonary Arterial Hypertension

Welch

Chung

2020

Genes

View full text Add to dashboard Cite

Pulmonary arterial hypertension (PAH) is a rare disease with high mortality despite recent therapeutic advances. The disease is caused by both genetic and environmental factors and likely gene–environment interactions. While PAH can manifest across the lifespan, pediatric-onset disease is particularly challenging because it is frequently associated with a more severe clinical course and comorbidities including lung/heart developmental anomalies. In light of these differences, it is perhaps not surprising that emerging data from genetic studies of pediatric-onset PAH indicate that the genetic basis is different than that of adults. There is a greater genetic burden in children, with rare genetic factors contributing to ~42% of pediatric-onset PAH compared to ~12.5% of adult-onset PAH. De novo variants are frequently associated with PAH in children and contribute to at least 15% of all pediatric cases. The standard of medical care for pediatric PAH patients is based on extrapolations from adult data. However, increased etiologic heterogeneity, poorer prognosis, and increased genetic burden for pediatric-onset PAH calls for a dedicated pediatric research agenda to improve molecular diagnosis and clinical management. A genomics-first approach will improve the understanding of pediatric PAH and how it is related to other rare pediatric genetic disorders.

show abstract

“…Rare deleterious variants in SOX17 have been found in a large cohort of whole-genome sequenced I/HPAH patients characterised by young age at diagnosis, some of these variants also segregated with the phenotype 8 . These findings were validated in a Japanese cohort of I/HPAH patients 68 . Another study involving whole-exome sequencing of 256 patients implicated SOX17 in the pathogenesis of PAH associated with congenital heart disease 69 .…”

Section: State Of the Artmentioning

confidence: 57%

The role of genomics and genetics in pulmonary arterial hypertension

Swietlik¹,

Gräf²,

Morrell³

2020

gcsp

View full text Add to dashboard Cite

[No abstract. Showing first paragraph of article]Although pulmonary hypertension (PH) had been recognised for centuries, it was not until the invention of cardiac catheterisation in the 1950s that enabled an accurate gene encoding bone morphogenetic protein receptor type 2, in patients with familial and clinical diagnosis. The discovery of heterozygous germline mutations in BMPR2, the idiopathic forms of pulmonary arterial hypertension (PAH) was another breakthrough in understanding the disease and initiated a new era in care of patients with this condition.

show abstract

SOX17 Mutations in Japanese Patients with Pulmonary Arterial Hypertension

Cited by 26 publications

References 10 publications

Molecular genetic framework underlying pulmonary arterial hypertension

Molecular genetic framework underlying pulmonary arterial hypertension

Genetics and Genomics of Pediatric Pulmonary Arterial Hypertension

The role of genomics and genetics in pulmonary arterial hypertension

Contact Info

Product

Resources

About