RESUMO
POPDC2 encodes for the Popeye domain-containing protein 2 which has an important role in cardiac pacemaking and conduction, due in part to its cAMP-dependent binding and regulation of TREK-1 potassium channels. Loss of Popdc2 in mice results in sinus pauses and bradycardia and morpholino knockdown of popdc2 in zebrafish results in atrioventricular (AV) block. We identified bi-allelic variants in POPDC2 in 4 families that presented with a phenotypic spectrum consisting of sinus node dysfunction, AV conduction defects and hypertrophic cardiomyopathy. Using homology modelling we show that the identified POPDC2 variants are predicted to diminish the ability of POPDC2 to bind cAMP. In in vitro electrophysiological studies we demonstrated that, while co-expression of wild-type POPDC2 with TREK-1 increased TREK-1 current density, POPDC2 variants found in the patients failed to increase TREK-1 current density. While patient muscle biopsy did not show clear myopathic disease, it showed significant reduction of the expression of both POPDC1 and POPDC2, suggesting that stability and/or membrane trafficking of the POPDC1-POPDC2 complex is impaired by pathogenic variants in any of the two proteins. Single-cell RNA sequencing from human hearts demonstrated that co-expression of POPDC1 and 2 was most prevalent in AV node, AV node pacemaker and AV bundle cells. Sinoatrial node cells expressed POPDC2 abundantly, but expression of POPDC1 was sparse. Together, these results concur with predisposition to AV node disease in humans with loss-of-function variants in POPDC1 and POPDC2 and presence of sinus node disease in POPDC2, but not in POPDC1 related disease in human. Using population-level genetic data of more than 1 million individuals we showed that none of the familial variants were associated with clinical outcomes in heterozygous state, suggesting that heterozygous family members are unlikely to develop clinical manifestations and therefore might not necessitate clinical follow-up. Our findings provide evidence for POPDC2 as the cause of a novel Mendelian autosomal recessive cardiac syndrome, consistent with previous work showing that mice and zebrafish deficient in functional POPDC2 display sinus and AV node dysfunction.
RESUMO
INTRODUCTION: Migraine is a prevalent neurological headache disorder. Due to challenges associated with finding effective treatment, many individuals with migraine feel compelled to explore alternative treatment strategies, such as blood donation, hypothesized to provide migraine relief. METHODS: Through logistic, Poisson, and Cox regression methods, we examined the links between migraine and blood donation activities in two population cohorts: Danish blood donors in the Scandinavian Donations and Transfusions Database (SCANDAT-DK, N >1 million) and the Danish Blood Donor Study (N ~ 100,000). RESULTS: SCANDAT-DK analyses showed no link between migraine and the propensity to become a blood donor among males (odds ratio [OR]Males = 0.95 [95% Confidence Interval: 0.86-1.04], and a reduced propensity among females ORFemales = 0.88 [0.83-0.93]). The incidence of migraine was not reduced upon blood donation (standardized incidence ratio [SIR]Males = 0.94 [0.83-1.06]; SIRFemales = 1.04 [0.99-1.10]). Donors with migraine demonstrated longer intervals between donations (hazard ratio [HR]Males = 0.87 [0.85-0.91], HRFemales = 0.80 [0.78-0.82]), and an increased risk of donor lapse (ORMales = 1.23 [1.14-1.32]; ORFemales = 1.28 [1.22-1.33]). Results were corroborated in DBDS using self-reported migraine. Genetic predisposition to migraine associated with longer intervals in females (HRFemales = 0.98 [0.97-0.99]), but not in males. DISCUSSION: Our findings do not support the hypothesis that blood donation serves as a viable treatment strategy among migraine patients. Future prospective investigations may help to elucidate the underlying biological mechanisms by which blood donation may influence migraine pathology.