A SHOX2 loss-of-function mutation underlying familial atrial fibrillation

Abstract

Atrial fibrillation (AF), as the most common sustained cardiac arrhythmia, is associated with substantially increased morbidity and mortality. Aggregating evidence demonstrates that genetic defects play a crucial role in the pathogenesis of AF, especially in familial AF. Nevertheless, AF is of pronounced genetic heterogeneity, and in an overwhelming majority of cases the genetic determinants underlying AF remain elusive. In the current study, 162 unrelated patients with familial AF and 238 unrelated healthy individuals served as controls were recruited. The coding exons and splicing junction sites of the SHOX2 gene, which encodes a homeobox-containing transcription factor essential for proper development and function of the cardiac conduction system, were sequenced in all study participants. The functional effect of the mutant SHOX2 protein was characterized with a dual-luciferase reporter assay system. As a result, a novel heterozygous SHOX2 mutation, c.580C>T or p.R194X, was identified in an index patient, which was absent from the 476 control chromosomes. Genetic analysis of the proband's pedigree revealed that the nonsense mutation co-segregated with AF in the family with complete penetrance. Functional assays demonstrated that the mutant SHOX2 protein had no transcriptional activity compared with its wild-type counterpart. In conclusion, this is the first report on the association of SHOX2 loss-of-function mutation with enhanced susceptibility to familial AF, which provides novel insight into the molecular mechanism underpinning AF, suggesting potential implications for genetic counseling and individualized management of AF patients.

A novel TBX5 mutation predisposes to familial cardiac septal defects and atrial fibrillation as well as bicuspid aortic valve

“…This study subjects comprised 178 unrelated adult patients suffering from both CHD and AF, who were consecutively recruited between February 2015 and March 2019 from the Chinese Han population. Diagnosis of CHD and various kinds of AF was made as described previously (Wang et al, 2016;Li et al, 2018b;Ma et al, 2019). The patients with rheumatic heart disease, ischemic heart disease, essential hypertension, or other recognized risk factors for AF were excluded.…”

Chamber-specific transcriptional responses in atrial fibrillation

“…Using a fold change threshold of no more than 0.667 or at least 1.5 and FDR less than 0.05, we observed that the majority of TFs were also dysregulated only within the AF+HF RA ( Figure 1D ; 140 unique TFs) or AF+HF LA ( Figure 1E ; 46 unique TFs), while only 9 TFs (~5% of total) met these criteria in both atria ( Figure 1, D and E ; and Supplemental Table 10 ). Several TFs dysregulated within LA CMN have previously been associated with predisposition to AF both in humans and in animal models, including PITX2 (fold change = 0.37, FDR = 2.42E-02) ( 27 , 49 ) and short stature homeobox protein 2 ( SHOX2 ; fold change = 0.08, FDR = 2.37E-31) ( 50 , 51 ). Additional TFs specifically dysregulated within human LA CMN have been linked with atrial gene regulation in murine models, including HOP homeobox ( 52 ) (fold change = 3.35, FDR = 8.31E-03) and paralogs of ETS variant 1 ( ETV1 ; ref.…”

The transcription factor Shox2 shapes thalamocortical neuron firing and synaptic properties

“…Shox2 is a super-conserved gene with 99% amino acid identity between human SHOX2 and mouse Shox2. A recent study found that two missense mutations within the human SHOX2 gene are associated with early-onset atrial fibrillation, likely caused by a defect in pacemaker activity 105,106 . In addition, while mice do not express the Shox gene, human SHOX and SHOX2 have 79% similar amino acid identity, and the same DNA-binding domains and putative phosphorylation sites.…”