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Published on: May 5, 2018
SMAD5 as a novel susceptibility gene for congenital patent ductus arteriosus
Hong Zhang1, Xiao-Qing Hu2, Yan-Jie Li3
1Department of Obstetrics, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200123, China.
Insights
New genetic variations in the SMAD5 gene are linked to patent ductus arteriosus (PDA), a common congenital heart defect (CHD). These SMAD5 variants impair cardiovascular development, offering insights for personalized PDA treatments.
Area of Science:
- Genetics and Molecular Biology
- Cardiovascular Research
- Developmental Biology
Background:
- Congenital heart disease (CHD) is a prevalent birth defect with a significant genetic component, yet many underlying genetic causes remain unknown.
- Patent ductus arteriosus (PDA) is a common type of CHD, contributing to infant mortality and morbidity globally.
- Identifying novel genetic factors is crucial for understanding CHD pathogenesis and developing targeted therapies.
Purpose of the Study:
- To identify and characterize novel genetic variations associated with congenital heart disease, specifically PDA.
- To investigate the functional impact of identified SMAD5 gene variants on cardiovascular development pathways.
- To explore the potential role of SMAD5 haplo-insufficiency in the genetic architecture of PDA.
Main Methods:
- Exome and Sanger sequencing were performed on a five-generation pedigree with PDA and 174 index CHD patients, alongside 218 unrelated controls.
- Functional analysis of novel SMAD5 variants (c.244A>T [p.(Lys82*)] and c.209G>T [p.(Arg70Ile)]) was conducted using dual-luciferase reporter assays.
- Assays measured the transactivation activity of SMAD5 on target genes, including NKX2.5, ID2, and BMP4, crucial for cardiovascular morphogenesis.
Main Results:
- Two novel heterozygous SMAD5 variants, p.(Lys82*) and p.(Arg70Ile), were identified in individuals with PDA and were absent in controls.
- Functional assays demonstrated that these SMAD5 variants significantly diminished the transactivation of NKX2.5 and impaired the synergistic activation of ID2 and BMP4.
- The identified variants suggest that SMAD5 haplo-insufficiency contributes to the pathogenesis of PDA in humans.
Conclusions:
- Novel SMAD5 variants are implicated in the etiology of patent ductus arteriosus, highlighting the gene's critical role in cardiovascular development.
- SMAD5 haplo-insufficiency represents a potential genetic mechanism underlying PDA in a subset of patients.
- These findings provide a basis for genetic counseling and the development of individualized medicine approaches for PDA.
Abstract:
Congenital heart disease (CHD), which represents the most common type of human birth defect affecting approximately 1% of all live births globally, is a leading cause of substantial infant mortality and morbidity worldwide. Although aggregating evidence has convincingly suggested a strong genetic basis underpinning CHD, the inherited components underlying CHD in most cases remain indefinite. Hence, the current investigation aimed to identify and characterize novel genetic variations underlying CHD. A five-generation pedigree with patent ductus arteriosus (PDA) and another group of 174 index patients with CHD were enrolled. In addition, 218 unrelated non-CHD people were employed as controls. Clinical assessments, along with exome-sequencing and Sanger-sequencing examinations, were performed in the study participants. The functional effects of the detected variations in the SMAD5 gene, which encodes a transcription factor required for proper cardiovascular morphogenesis, were measured by dual-luciferase reporter assays. Two new SMAD5 variants, NM_005903.7: c.244 A > T; p.(Lys82*) and NM_005903.7: c.209G > T; p.(Arg70Ile), were detected in a heterozygous status in the PDA pedigree and one PDA case out of the 174 index patients affected with CHD, respectively. Neither of the two SMAD5 variations was observed in the 436 control chromosomes. Quantitative biochemical assays using dual-reporter genes revealed that the Lys82*- or Arg70Ile-mutant SMAD5 possessed diminished transactivation of NKX2.5, an established CHD-causative gene. Furthermore, the Lys82* or Arg70Ile variation nullified or significantly reduced the synergistic transactivation of ID2 between SMAD5 and BMP4, and both ID2 and BMP4 had been causally implicated in the pathogenesis underpinning CHD. The present findings indicate that SMAD5 haplo-insufficient variants contribute to PDA in humans, which sheds more light on the genetic architecture of PDA and implies a potential target for genetic counseling and individualized medicine of PDA in a subgroup of patients.
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