Clinical And Pathological Features Of Podocyte Injury Induced By R246Q Mutation In WT1

Objective:Focal Segmental Glomerulosclerosis(FSGS)is a common pathologic pattern in glomeruli of many glomerular diseases rather than a disease entity.Mutations in a number of genes encoding proteins essential for structure and function of glomeruli are known to cause familial FSGS.WT1(Wilms tumor suppressor gene 1)gene mutation is known for genitourinary malformation/Wilms tumor,which often leads to pseudohermaphroditism/Wilms tumor in children.In adult patients,it is uncommon to find patients with only kidney diseases without genitourinary malformation.To summarize the clinical and pathological characteristics of glomerular disease with WT1 gene mutation,we reviewed the articles about WT1 mutation-associated nephropathy.Methods :We report a case of a 44-year-old Chinese woman who was diagnosed with FSGS by renal biopsy and found to carry a newly documented mutation of WT1-R246 Q.The whole blood samples of the proband and her family members were sent to Mygenostics(Beijing,China)for genomic DNA analysis using the ‘Glomerular diseases panel' as listed in the table1.The Pedigree of the patient's family was drawn.The Human Gene Mutation Database(HGMD)were used to find out the mutation sites of WT1 gene about isolate nephrotic syndrome/proteinuria till the Feb.2020,the sites' location in the WT1 gene were drawn in the picture.We also reviewed the articles about WT1 mutation in kidney disease to summarize the clinical and pathological characteristics of WT1 mutation-associated nephropathy.Results:Here we report a case of a 44-year-old Chinese woman who was diagnosed with FSGS by renal biopsy and found to carry a newly documented mutation of WT1.Her uncle died of uremia and her father's younger male cousin was suffering from uremia and receiving maintenance hemodialysis.Her renal histological findings demonstrated FSGS with lots of foam cells in renal interstitium.Gene sequencing analysis revealed a missense mutation(R246Q)in WT1,which was first reported in two Northern European kindreds and has been functionally tested in zebrafish and human podocyte recently.50 mutation sites of WT1 about isolate kidney disease were found which are mostly focus on exon 8 and 9.Only 2 mutation sites are about slowly progressive nonsyndromic proteinuria which are closely located in the gene of WT1.The rest mutation sites are mostly associated with early-onset,rapidly progressive steroid-resistant nephrotic syndrome(SRNS)in children.There are few reports of WT1 related nephrotic pathology,among which diffuse mesangial sclerosis(DMS)is considered as a specific pathological manifestation,followed by FSGS.The WT1 mutation associated nephropathy was always rapidly progressive,but the patients with WT1-R246 Q mutation showed a more slowly way of the progression in renal function.Conclusion: This case report further confirms the pathogenicity of the R246 Q mutation of WT1 in FSGS and represents the first case in the Chinese population.In the family of the patient,this mutation showed a significant heterogeneity in clinical phenotypes.Gene testing is necessary to make early diagnosis such that therapeutic regimen can be adjusted for steroid-resistant nephrotic syndrome and familial nonsyndromic FSGS.