GATA5 loss-of-function mutations associated with congenital bicuspid aortic valve

Abstract

Bicuspid aortic valve (BAV) is the most common form of congenital cardiovascular defect in humans worldwide and is responsible for substantial morbidity and mortality. Accumulating evidence has demonstated that genetic risk factors are involved in the pathogenesis of BAV. However, BAV is genetically heterogeneous and the genetic basis underlying BAV in a large number of patients remains unknown. In the present study, the coding regions and splice junction sites of the GATA5 gene, which codes for a zinc-finger transcription factor crucial for the normal development of the aortic valve, was sequenced initially in 110 unrelated patients with BAV. The available relatives of the mutation carriers and 200 unrelated healthy individuals used as controls were subsequently genotyped for GATA5. The functional effect of the mutations was characterized by using a luciferase reporter assay system. As a result, two novel heterozygous GATA5 mutations, p.Y16D and p.T252P, were identified in two families with autosomal dominant inheritance of BAV, respectively. The variations were absent in 400 control chromosomes and the altered amino acids were completely conserved evolutionarily. Functional assays revealed that the two GATA5 mutants were associated with significantly reduced transcriptional activity compared with their wild-type counterpart. To the best of our knowledge, this is the first study on the association of GATA5 loss-of-function mutations with enhanced susceptibility to BAV, providing novel insight into the molecular mechanism involved in human BAV and suggesting a potential role for the early prophylaxis and personalized treatment of this common congenital heart disease.

Genetic basis of aortic valvular disease

“…Additional reports support this finding that mutations in NOTCH1 cause malformations of the right and left sided cardiac outflow tract within families [11,14,15]. The other gene linked to BAV in humans is GATA5 , where rare sequence variants in GATA5 were identified in patients with BAV by multiple groups [16,17,18]. Similar to NOTCH1 , mutations in GATA5 have reported in a spectrum of CHD, including tetralogy of Fallot [19,20,21].…”

Calcific aortic stenosis

“…However, despite the evidence of a strong inheritance pattern for some cases of bicuspid aortic valve with an incomplete penetrance, the genetic architecture of calcific AS is still poorly understood 145 . So far, variants of NOTCH1 and GATA binding protein 5 ( GATA5 ) have been associated with bicuspid aortic valves in humans 97;146;147 . NOTCH1 mutations explain approximately 4% of sporadic cases of AS that occurs in the context of a bicuspid aortic valve 148;149 .…”

TBX20 loss-of-function mutation associated with familial dilated cardiomyopathy

“…As a part of a conserved regulatory network, these core cardiac transcription factors physically interact with each other to finely regulate cardiac development and structural remodeling [6][7][8]. Therefore, it is not surprising that an increasing number of mutations in these core cardiac transcription factors, especially for the most extensively investigated NKX2-5, GATA4, GATA5, GATA6, TBX5, and TBX20, have been identified in patients with various CHDs or cardiac arrhythmias [9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25]. More interestingly, mutations in some cardiac transcription factors, such as NKX2-5, GATA4, GATA5, GATA6 and TBX5, have also been associated with isolated DCM in humans [26][27][28][29][30][31][32].…”