Structural insight, mutation and interactions in human Beta-catenin and SOX17 protein: A molecular-level outlook for organogenesis

Banerjee, Arundhati; Ray, Sujay

doi:10.1016/j.gene.2017.01.026

Cited by 7 publications

(6 citation statements)

References 38 publications

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“…The SOX family is characterised by a highly conserved HMG box, a sequence specific DNA-binding domain, where most of the missense variants are located in the HMG box. Site-directed mutagenesis studies have shown that missense mutations within this region can impair both direct DNA binding [24] and SOX17/β-catenin protein complex interactions [25] demonstrating that sequence alteration within this domain have a strong function impact on the SOX17 protein.…”

Section: Discussionmentioning

confidence: 99%

An emerging phenotype of pulmonary arterial hypertension patients carryingSOX17variants

et al. 2022

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IntroductionThe phenotype of pulmonary arterial hypertension (PAH) patients carrying SOX17 pathogenic variants remains mostly unknown.MethodsWe report the genetic analysis findings, characteristics and outcomes of patients with heritable PAH carrying SOX17 variants from the French Pulmonary Hypertension Network.ResultsTwenty patients and eight unaffected relatives were identified. The median (min-max) age at diagnosis was 17 years (2–53), with a female-to-male ratio of 1.5. At diagnosis, most of the patients (74%) were in functional class III or IV with severe hemodynamic compromise, including a median pulmonary vascular resistance (PVR) of 14.0 (4.2–31.5) Wood units (WU). An associated congenital heart disease (CHD) was found in 7 PAH patients (35%). Patients with CHD-associated PAH were significantly younger at diagnosis than PAH patients without CHD. Four patients (20%) suffered from recurrent haemoptysis requiring repeated arterial embolisations. Thirteen out of 16 patients (81%) of whom imaging was available displayed chest computed tomography abnormalities, including dilated, tortuous pulmonary vessels, ground-glass opacities as well as bronchial and non-bronchial arteries anomalies. After a median follow-up of 47 months (1–591 months), 10 patients underwent lung transplantation and one patient benefited from a heart-lung transplantation due to associated CHD. Histopathologic analysis of lung explants showed a congested lung architecture with severe pulmonary arterial remodelling, subpleural vessel dilation and numerous haemorrhagic foci.ConclusionsPAH due to SOX17 pathogenic variants is a severe phenotype, frequently associated with CHD, haemoptysis and radiologic abnormalities. Pathologic assessment reveals severe pulmonary arterial remodelling and malformations affecting pulmonary vessels and thoracic systemic arteries.

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Section: Discussionmentioning

confidence: 99%

An emerging phenotype of pulmonary arterial hypertension patients carryingSOX17variants

et al. 2022

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“…2b ). Previously reported site-directed mutagenesis studies indicate that similar point mutations within this region (M76A, G103R) can impair both direct DNA binding [ 69 ] and complex nucleoprotein interactions, including SOX17/β-catenin protein complexes, at target gene promoters [ 70 , 71 ]. This suggests that haploinsufficiency with loss of function alleles is the likely mechanism of SOX17 risk in PAH-CHD.…”

Section: Discussionmentioning

confidence: 99%

Rare variants in SOX17 are associated with pulmonary arterial hypertension with congenital heart disease

et al. 2018

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BackgroundPulmonary arterial hypertension (PAH) is a rare disease characterized by distinctive changes in pulmonary arterioles that lead to progressive pulmonary arterial pressures, right-sided heart failure, and a high mortality rate. Up to 30% of adult and 75% of pediatric PAH cases are associated with congenital heart disease (PAH-CHD), and the underlying etiology is largely unknown. There are no known major risk genes for PAH-CHD.MethodsTo identify novel genetic causes of PAH-CHD, we performed whole exome sequencing in 256 PAH-CHD patients. We performed a case-control gene-based association test of rare deleterious variants using 7509 gnomAD whole genome sequencing population controls. We then screened a separate cohort of 413 idiopathic and familial PAH patients without CHD for rare deleterious variants in the top association gene.ResultsWe identified SOX17 as a novel candidate risk gene (p = 5.5e−7). SOX17 is highly constrained and encodes a transcription factor involved in Wnt/β-catenin and Notch signaling during development. We estimate that rare deleterious variants contribute to approximately 3.2% of PAH-CHD cases. The coding variants identified include likely gene-disrupting (LGD) and deleterious missense, with most of the missense variants occurring in a highly conserved HMG-box protein domain. We further observed an enrichment of rare deleterious variants in putative targets of SOX17, many of which are highly expressed in developing heart and pulmonary vasculature. In the cohort of PAH without CHD, rare deleterious variants of SOX17 were observed in 0.7% of cases.ConclusionsThese data strongly implicate SOX17 as a new risk gene contributing to PAH-CHD as well as idiopathic/familial PAH. Replication in other PAH cohorts and further characterization of the clinical phenotype will be important to confirm the precise role of SOX17 and better estimate the contribution of genes regulated by SOX17.Electronic supplementary materialThe online version of this article (10.1186/s13073-018-0566-x) contains supplementary material, which is available to authorized users.

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“…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 ]. These data suggest that haploinsufficiency with complete or partial loss of function alleles is the likely mechanism of SOX17 risk in PAH.…”

Section: Genetics Of Pediatric Pah—current Knowledgementioning

confidence: 99%

Genetics and Genomics of Pediatric Pulmonary Arterial Hypertension

Welch

Chung

2020

Genes

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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.

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Structural insight, mutation and interactions in human Beta-catenin and SOX17 protein: A molecular-level outlook for organogenesis

Cited by 7 publications

References 38 publications

An emerging phenotype of pulmonary arterial hypertension patients carryingSOX17variants

An emerging phenotype of pulmonary arterial hypertension patients carryingSOX17variants

Rare variants in SOX17 are associated with pulmonary arterial hypertension with congenital heart disease

Genetics and Genomics of Pediatric Pulmonary Arterial Hypertension

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