Aarhus University Hospital, Denmark
Joshi Shivani was awarded an international mobility PhD scholarship from Aarhus University in 2010 and is currently pursuing a PhD in Translational Molecular Medicine at Aarhus. Her research is focused on studying the mutation spectrum in Danish patients with steroid resistant nephrotic syndrome; identifying new genes in steroid sensitive nephrotic syndrome and using animal models to understand the pathophysiology of nephrotic syndrome. She has presented her work at various national and international conferences. She has won several research grants in connection to her PhD, published a review on genetics of Nephrotic syndrome, is a member of Danish Society of Nephrology and is a Youth Goodwill Ambassador for Denmark.
Variations in genes encoding glomerular proteins like NPHS1, NPHS2 and INF2 have shown to be associated with steroid resistant nephrotic syndrome (SRNS). Patients with genetic forms of SRNS are usually unresponsive to immunosuppressive therapy and are at risk of developing end stage renal disease. Thus, knowing the underlying genetic etiology has important implications in therapeutic decisions. The study aimed to establish a rapid and highly sensitive method for scanning variations in SRNS genes and to determine their spectrum in the Danish patients. Variations in coding regions of NPHS1 and NPHS2 as well as hot spot exons of INF2 were scanned using high-resolution melting analysis and confirmed by bi-directional sequencing in 40 Danish patients diagnosed with sporadic SRNS. This analysis identified some previously described pathogenic variations like c.550G>A in INF2, c.686G>A and c.855_856del in NPHS2 as well as c.349G>A, c.1223G>A, c.3047G>A and c.3230A>G in NPHS1. In both patients and controls we also identified known polymorphisms in NPHS2 and NPHS1. In addition, it was identified that some novel exonic and intronic variants of unkown significance that are predicted to affect splicing of NPHS1 and INF2. Interestingly, while most patients are compound heterozygous for potential pathogenic variations in NPHS1, some have single heterozygous variations in both NPHS1 and NPHS2, respectively. Our results show that 1) high-resolution melting analysis is a rapid and sensitive technique for mutation screening of SRNS genes and 2) the identified variations do explain the occurrence of SRNS in approximately 50% of the patients suggesting further loci heterogeneity in Danish patients with SRNS.