RGD Reference Report - SOX17 Loss-of-Function Mutation Underlying Familial Pulmonary Arterial Hypertension. - Rat Genome Database

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SOX17 Loss-of-Function Mutation Underlying Familial Pulmonary Arterial Hypertension.

Authors: Wang, Tian-Ming  Wang, Shan-Shan  Xu, Ying-Jia  Zhao, Cui-Mei  Qiao, Xiao-Hui  Yang, Chen-Xi  Liu, Xing-Yuan  Yang, Yi-Qing 
Citation: Wang TM, etal., Int Heart J. 2021 May 29;62(3):566-574. doi: 10.1536/ihj.20-711. Epub 2021 May 1.
RGD ID: 329853326
Pubmed: PMID:33952808   (View Abstract at PubMed)
DOI: DOI:10.1536/ihj.20-711   (Journal Full-text)

Pulmonary arterial hypertension (PAH) refers to a rare, progressive disorder that is characterized by occlusive pulmonary vascular remodeling, resulting in increased pulmonary arterial pressure, right-sided heart failure, and eventual death. Emerging evidence from genetic investigations of pediatric-onset PAH highlights the strong genetic basis underpinning PAH, and deleterious variants in multiple genes have been found to cause PAH. Nevertheless, PAH is of substantial genetic heterogeneity, and the genetic defects underlying PAH in the overwhelming majority of cases remain elusive. In this investigation, a consanguineous family suffering from PAH transmitted as an autosomal-dominant trait was identified. Through whole-exome sequencing and bioinformatic analyses as well as Sanger sequencing analyses of the PAH family, a novel heterozygous SOX17 mutation, NM_022454.4: c.379C>T; p. (Gln127*), was found to co-segregate with the disease in the family, with complete penetrance. The nonsense mutation was neither observed in 612 unrelated healthy volunteers nor retrieved in the population genetic databases encompassing the Genome Aggregation Database, the Exome Aggregation Consortium database, and the Single Nucleotide Polymorphism database. Biological analyses using a dual-luciferase reporter assay system revealed that the Gln127*-mutant SOX17 protein lost the ability to transcriptionally activate its target gene NOTCH1. Moreover, the Gln127*-mutant SOX17 protein exhibited no inhibitory effect on the function of CTNNB1-encode β-catenin, which is a key player in vascular morphogenesis. This research firstly links SOX17 loss-of-function mutation to familial PAH, which provides novel insight into the molecular pathogenesis of PAH, suggesting potential implications for genetic and prognostic risk evaluation as well as personalized prophylaxis of the family members affected with PAH.



RGD Manual Disease Annotations    Click to see Annotation Detail View

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
SOX17HumanPulmonary Arterial Hypertension  IAGP DNA:nonsense mutation:CDS:p.Q127* (human)RGD 
Sox17RatPulmonary Arterial Hypertension  ISOSOX17 (Homo sapiens)DNA:nonsense mutation:CDS:p.Q127* (human)RGD 
Sox17MousePulmonary Arterial Hypertension  ISOSOX17 (Homo sapiens)DNA:nonsense mutation:CDS:p.Q127* (human)RGD 

Phenotype Annotations    Click to see Annotation Detail View

Manual Human Phenotype Annotations - RGD

Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
SOX17HumanIncreased pulmonary capillary wedge pressure  IAGP DNA:nonsense mutation:CDS:p.Q127* RGD 
SOX17HumanIncreased pulmonary vascular resistance  IAGP DNA:nonsense mutation:CDS:p.Q127* RGD 
SOX17HumanPulmonary arterial hypertension  IAGP DNA:nonsense mutation:CDS:p.Q127* RGD 
Objects Annotated

Genes (Rattus norvegicus)
Sox17  (SRY-box transcription factor 17)

Genes (Mus musculus)
Sox17  (SRY (sex determining region Y)-box 17)

Genes (Homo sapiens)
SOX17  (SRY-box transcription factor 17)


Additional Information