Introduction Mutations in genes encoding nucleoporins (NUPs; components of nuclear pore complexes [NPCs]), such as NUP93 , have been reported to cause steroid-resistant nephrotic syndrome (SRNS) or focal segmental glomerulosclerosis (FSGS), which often progresses to end-stage renal disease (ESRD) in childhood. The expression of NUP93 in renal or extrarenal tissues, and the mechanism by which NUP93 mutations cause this renal phenotype, remain unclear. Methods The expression of NUP93 in normal control kidney and in a patient with FSGS carrying NUP93 mutations was examined by immunofluorescence analysis. The expression of NUP93 in blood cells was analyzed by Western blot analysis. Results Immunofluorescence analysis detected NUP93 expression in nuclei of all glomerular and tubulointerstitial cells in human kidneys. Whole-exome sequencing identified a compound heterozygous NUP93 mutation comprising a novel missense mutation p.Arg525Trp, and a previously reported mutation, p.Tyr629Cys, in a patient with FSGS that developed ESRD at the age of 6 years. In the patient’s kidney, the intensity of NUP93 immunofluorescence was significantly decreased in the nuclei of both glomerular and extraglomerular cells. The expression of CD2-associated protein (CD2AP) and nephrin in the patient’s podocytes was relatively intact. The amount of NUP93 protein was not significantly altered in the peripheral blood mononuclear cells of the patient. Conclusion NUP93 is expressed in the nuclei of all the cell types of the human kidney. Altered NUP93 expression in glomerular cells as well as extraglomerular cells by NUP93 mutations may underlie the pathogenic mechanism of SRNS or FSGS.

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Background The precise mechanism of hyponatremia in Kawasaki disease (KD) remains elusive because assessment of volume status based on serial changes in body weight is lacking in previous reports. Methods Seventeen patients who were diagnosed with KD and hyponatremia (serum sodium levels <135 mmol/L) were analyzed. Volume status was assessed based on serial changes in body weight. Plasma arginine vasopressin (ADH), urine electrolytes, and serum cytokine levels were measured on diagnosis of hyponatremia. An increase in body weight by >3% was defined as hypervolemia and a decrease in body weight by >3% was defined as hypovolemia. Results The volume status was hypervolemic in three patients (18%), euvolemic in 14 (82%), and hypovolemic in none (0%). Five (29%) patients were diagnosed with “syndrome of inappropriate secretion of antidiuretic hormone” (SIADH) and no patients were diagnosed with hypotonic dehydration. The contribution of decreased total exchangeable cations (salt loss) to hyponatremia (5.9% [interquartile range, 4.3%, 6.7%]) was significantly larger than that of increased total body water (−0.7% [−1.8%, 3.1%]) (P = 0.004). Serum interleukin‐6 levels were elevated in all of the nine patients who were evaluated. Among the 12 (71%) patients who did not meet the criteria of SIADH and hypotonic dehydration, plasma ADH levels were inappropriately high in ten patients. These patients were also characterized by euvolemic or hypervolemic hyponatremia and salt loss, which might be compatible with a diagnosis of SIADH. Conclusions Our study shows that hyponatremia in KD is euvolemic or hypervolemic and is associated with nonosmotic secretion of ADH and salt loss in the majority of patients.

Mutations in LAMB2 , encoding laminin β 2 , cause Pierson syndrome and occasionally milder nephropathy without extrarenal abnormalities. The most deleterious missense mutations that have been identified affect primarily the N-terminus of laminin β 2 . On the other hand, those associated with isolated nephropathy are distributed across the entire molecule, and variants in the β 2 LEa-LF-LEb domains are exclusively found in cases with isolated nephropathy. Here we report the clinical features of mild isolated nephropathy associated with 3 LAMB2 variants in the LEa-LF-LEb domains (p.R469Q, p.G699R, and p.R1078C) and their biochemical characterization. Although Pierson syndrome missense mutations often inhibit laminin β 2 secretion, the 3 recombinant variants were secreted as efficiently as WT. However, the β 2 variants lost pH dependency for heparin binding, resulting in aberrant binding under physiologic conditions. This suggests that the binding of laminin β 2 to negatively charged molecules is involved in glomerular basement membrane (GBM) permselectivity. Moreover, the excessive binding of the β 2 variants to other laminins appears to lead to their increased deposition in the GBM. Laminin β 2 also serves as a potentially novel cell-adhesive ligand for integrin α 4 β 1 . Our findings define biochemical functions of laminin β 2 variants influencing glomerular filtration that may underlie the pathogenesis of isolated nephropathy caused by LAMB2 abnormalities.

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