👤 Bruno Gavillet

Hemolytic disease of the fetus and newborn (HDFN) is a potentially life-threatening condition caused by maternal alloimmunization against fetal red blood cell (RBC) antigens. While most cases involve well-characterized antibodies such as anti-D, anti-c, or anti-K, antibodies against low-prevalence antigens (LPAs) - particularly those within the MNS blood group system - remain underrecognized and underreported. We report a case of maternal alloimmunization against the paternally inherited LPA MUT (MNS35), carried on a hybrid glycophorin ( This case supports the pathogenicity of anti-MUT as a cause of severe HDFN. It underscores the diagnostic challenges posed by antibodies against LPAs and highlights the importance of extended serological, molecular, and functional testing. Crossmatching maternal plasma with paternal RBCs and systematic evaluation of serological discrepancies can reveal otherwise undetectable alloantibodies. Early identification, functional assessment, and multidisciplinary management are key to optimizing outcomes in pregnancies complicated by rare RBC alloimmunization. Anti-MUT should be considered a clinically significant antibody with the potential to cause severe HDFN, warranting proactive perinatal surveillance. Show less

The voltage-gated Na(+) channels (Na(v)) form a family composed of 10 genes. The COOH termini of Na(v) contain a cluster of amino acids that are nearly identical among 7 of the 10 members. This COOH-terminal sequence, PPSYDSV, is a PY motif known to bind to WW domains of E3 protein-ubiquitin ligases of the Nedd4 family. We recently reported that cardiac Na(v)1.5 is regulated by Nedd4-2. In this study, we further investigated the molecular determinants of regulation of Na(v) proteins. When expressed in HEK-293 cells and studied using whole cell voltage clamping, the neuronal Na(v)1.2 and Na(v)1.3 were also downregulated by Nedd4-2. Pull-down experiments using fusion proteins bearing the PY motif of Na(v)1.2, Na(v)1.3, and Na(v)1.5 indicated that mouse brain Nedd4-2 binds to the Na(v) PY motif. Using intrinsic tryptophan fluorescence imaging of WW domains, we found that Na(v)1.5 PY motif binds preferentially to the fourth WW domain of Nedd4-2 with a K(d) of approximately 55 muM. We tested the binding properties and the ability to ubiquitinate and downregulate Na(v)1.5 of three Nedd4-like E3s: Nedd4-1, Nedd4-2, and WWP2. Despite the fact that along with Nedd4-2, Nedd4-1 and WWP2 bind to Na(v)1.5 PY motif, only Nedd4-2 robustly ubiquitinated and downregulated Na(v)1.5. Interestingly, coexpression of WWP2 competed with the effect of Nedd4-2. Finally, using brefeldin A, we found that Nedd4-2 accelerated internalization of Na(v)1.5 stably expressed in HEK-293 cells. This study shows that Nedd4-dependent ubiquitination of Na(v) channels may represent a general mechanism regulating the excitability of neurons and myocytes via modulation of channel density at the plasma membrane. Show less