Key result
Novel SHOX2 loss-of-function mutation linked to familial AF causes complete loss of transcriptional activation.
Case-Control (n=400)
Absolute Event Rate: 1% vs 16%
p-value: p=0.00035
A novel SHOX2 loss-of-function mutation (p.R194X) is associated with enhanced susceptibility to familial atrial fibrillation, providing new insights into the genetic basis of the disease.
May implicate SHOX2 loss-of-function in familial AF risk; extends genetic insights but leaves clinical utility open.
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.
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Li et al. (2018) conducted a case-control in Familial atrial fibrillation (n=400). SHOX2 loss-of-function mutation (p.R194X) vs. Wild-type SHOX2 (non-carriers) was evaluated on Transcriptional activation of the BMP4 promoter (fold activation) (p=0.00035). A novel heterozygous SHOX2 loss-of-function mutation (p.R194X) was identified in a family with atrial fibrillation and resulted in a complete loss of transcriptional activation of target genes.
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