https://doi.org/10.1007/s00392-024-02526-y
1Universitätsklinikum Heidelberg Institut für Humangenetik Heidelberg, Deutschland; 2Universitätsklinikum Heidelberg Klinik für Innere Med. III, Kardiologie, Angiologie u. Pneumologie Heidelberg, Deutschland
Introduction
The Shox2 gene is a key player in heart development, significantly influencing atrial tissue
specification and the development of the sinoatrial node, the heart’s primary pacemaker.
Mutations in the SHOX2 gene can lead to atrial arrhythmias such as atrial fibrillation (AF) and
sinus node dysfunction, resulting in irregular heart rhythms and severe cardiac complications.
Various heterozygous SHOX2 variants have been identified and functionally characterized in
patients with early-onset AF and sinus node dysfunction, a detailed investigation of
heterozygous knockout mice, which closely mirror the human condition, has not been
conducted yet. This study aims to elucidate the mechanisms underlying SHOX2-dependent
atrial arrhythmias by investigating adult heterozygous Shox2 knockout mice and patientspecific
induced pluripotent stem cells (iPSCs).
Methods & Results
Our study extends the understanding of the Shox2 regulatory network by exploring its role in
adult heterozygous Shox2 knockout mice. Expression analyses initially revealed no significant
differences between Shox2-deficient and wildtype right atrial tissues. However, genderspecific
analysis unveiled remarkable expression differences, particularly in developmental
relevant genes such as Nkx2.5, in addition to genes involved in cardiac calcium homeostasis,
such as Ryr2 and Ncx1. Interestingly, electrophysiological studies, including ECG and patchclamp
analyses demonstrated alterations that may be related to impaired calcium
homeostasis. We have observed a significant increase in the upstroke velocity in atrial
cardiomyocytes of the heterozygous mouse model. This phenomenon may be attributed to
alterations in sodium or calcium homeostasis. Similar findings were also identified in
cardiomyocytes derived from patient-specific iPSCs. In addition, we have detected a
prolonged PQ interval, which has also been demonstrated in AF patients carrying SHOX2
variants.
Discussion
This study provides insight into the relationship between SHOX2 haploinsufficiency and atrial
rhythm disturbances, and the parallels between the mouse model and human pathology.
Notably, atrial arrhythmias exhibit gender differences in prevalence, incidence, and outcomes.
Our findings provide initial evidence that sex-related differences in AF pathophysiology may
in part be mediated through Shox2-dependent gene regulatory mechanisms. These findings
emphasize the importance of considering sex-specific aspects in the assessment and
treatment of atrial arrhythmias.