title: Secondary focal and segmental glomerulosclerosis associated with single-nucleotide polymorphisms in the genes encoding complement factor H and C3.
abstract: Genetic causes of focal and segmental glomerulosclerosis (FSGS) typically involve mutations and allele variants of genes expressed in podocytes or, more rarely, glomerular basement membranes. In this report, we describe a 60-year-old woman with chronic kidney disease whose kidney biopsy showed FSGS. Immunoglobulins and C3 were undetectable in immunofluorescence studies. Electron microscopy showed subendothelial fluffy granular material with occasional double-contour formation suggestive of capillary wall injury and prompting work-up for a prothrombotic state. Evaluation of the alternative pathway of complement showed a novel polymorphism in short consensus repeat (SCR) 12 of complement factor H (CFH; c.2195C>T, p.Thr732Met) and a previously reported but largely uncharacterized polymorphism in complement factor C3 (c.463A>C, p.Lys155Gln). Dysregulation of the alternative pathway is associated with atypical hemolytic syndrome and dense deposit disease, but heretofore has not been associated with FSGS. This case highlights the expanding spectrum of complement-mediated glomerular disease and shows that FSGS with features of capillary wall injury should prompt evaluation for abnormalities in the alternative pathway. This case also expands the list of genetic polymorphisms that can be associated with an FSGS phenotype.
authors.affiliation: Division of Anatomic Pathology, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USA. sethi.sanjeev@mayo.edu
authors.forename: Sanjeev
authors.initials: S
authors.lastname: Sethi
authors.forename: Fernando C
authors.initials: FC
authors.lastname: Fervenza
authors.forename: Yuzhou
authors.initials: Y
authors.lastname: Zhang
authors.forename: Richard J H
authors.initials: RJ
authors.lastname: Smith
mesh_terms: D003176:Complement C3 / Q000235:genetics*; D017242:Complement Factor H / Q000235:genetics; D003170:Complement Pathway, Alternative / Q000235:genetics; D005260:Female; D005923:Glomerulosclerosis, Focal Segmental / Q000235:genetics* / Q000473:pathology; D006801:Humans; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D020539:Sequence Analysis, Protein
chemical_list: C493495:CFH protein, human; D003176:Complement C3; D017242:Complement Factor H