A genome-wide association research published in the Annals of the Rheumatic Diseases recently revealed auxilin as the first genetic susceptibility factor involved in neonatal lupus erythematosus (NLE) that modulates cardiac function.
The study carried out by a group of Swedish researchers involved population-based cohort of families with children diagnosed with congenital heart block (CHB). The study evaluated >500000 single nucleotide polymorphisms (SNPs) using microarrays, RNA sequencing, PCR, western blot, immunohistochemistry, immunofluorescence, and flow cytometry. The researchers identified DNAJC6 as a novel foetal susceptibility gene with lower cardiac expression related to the disease risk genotype. They further showed that foetal cardiomyocytes lacking auxilin, a protein encoded by DNAJC6, have aberrant connection and Ca2+ homoeostasis in culture, as well as diminished Cav 1.3 calcium channel cell surface expression. In utero, Doppler echocardiography of auxilin-deficient embryonic mice exhibited cardiac NLE abnormalities, including an aberrant heart rhythm with atrial and ventricular ectopias, as well as prolonged atrioventricular time intervals.
The probability of NLE in children of rheumatic female patients with autoantibodies to the Ro/SSA and La/SSB antigens is comparatively high. Skin rash and CHB have been identified as the most common manifestations of NLE. CHB generally develops between weeks 18–24 of gestation and is often detected upon presentation of the signs of bradycardia and complete AV block in fetus. Auxilin plays a paramount role in maintaining normal calcium homoeostasis and establishing the functional networks in cardiac cells. The CHB-associated genetic mutation, resulting in decreased auxilin expression, may thus adversely impair both mechanical and electrical fetal myocardial functions.
Present study identifying fetal genetic variants conferring risk of CHB and their adverse effects on cardiac function unfolds novel avenues in developing screening and therapeutic strategies.
Reference: Meisgen S, Hedlund M, Ambrosi A, et al. Auxilin is a novel susceptibility gene for congenital heart block which directly impacts fetal heart function [published online ahead of print, 2022 Apr 25]. Ann Rheum Dis. 2022; annrheumdis-2021-221714.