A gain-of-function ACTC1 3'UTR mutation that introduces a miR-139-5p target site may be associated with a dominant familial atrial septal defect.

Ye Wang,Xinwei Du,Lincai Ye,Zhen Zhang,Haifa Hong,Zaiwei Zhou,Jun Jiang

doi:10.1038/srep25404

Ye Wang, Xinwei Du + Show 5 more

Open Access

https://doi.org/10.1038/srep25404

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Abstract

The ostium secundum atrial septal defect (ASDII) is the most common type of congenital heart disease and is characterized by a left to right shunting of oxygenated blood caused by incomplete closure of the septum secundum. We identified a familial form of isolated ASDII that affects four individuals in a family of five and shows autosomal dominant inheritance. By whole genome sequencing, we discovered a new mutation (c.*1784T > C) in the 3′-untranslated region (3′UTR) of ACTC1, which encodes the predominant actin in the embryonic heart. Further analysis demonstrated that the c.*1784T > C mutation results in a new target site for miRNA-139-5p, a microRNA that is involved in cell migration, invasion, and proliferation. Functional analysis demonstrated that the c.*1784T > C mutation specifically downregulates gene expression in a luciferase assay. Additionally, miR-139-5p mimic causes further decrease, whereas miR-139-5p inhibitor can dramatically rescue the decline in gene expression caused by this mutation. These findings suggest that the familial ASDII may be a result of an ACTC1 3′UTR gain-of-function mutation caused by the introduction of a new miR-139-5p target site. Our results provide the first evidence of a pathogenic mutation in the ACTC1 3′UTR that may be associated with familial isolated ASDII.

Highlights

Congenital heart disease (CHD) is the most common type of the birth defect
The results suggest that c.*1784T > C may be a pathogenic gain-of-function mutation within the ACTC1 3′ -untranslated region (3′ UTR) mutation that accounts for the ASDII within this family
Four of the five individuals in the family had a similar clinical expression and a diagnosis of ASDII (Fig. 1C), which is characterized by a left to right shunting of oxygenated blood caused by incomplete closure of the septum secundum

Summary

Introduction

Congenital heart disease (CHD) is the most common type of the birth defect. More than 50% of CHDs are caused by sporadic atrial septal defects (ASDs) or ventricular septal defects (VSDs). Several pathogenic mutations (p.M123V, p.M178L, p.E101K) in ACTC1 have been identified in families with isolated ASDII11,12. Whole genome sequencing revealed a mutation in the 3′ -untranslated region (3′ UTR) of the ACTC1 genomic region on chromosome 15q14 (c.*1784T > C variant) Screening of this family indicated that the mutation is associated with isolated ASDII with autosomal dominant inheritance. The results suggest that c.*1784T > C may be a pathogenic gain-of-function mutation within the ACTC1 3′ UTR mutation that accounts for the ASDII within this family. This is the first demonstration of a mutation in the 3′ UTR of ACTC1 that may result in the occurrence of autosomal-dominant isolated ASDII

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