Cosegregation of Focal Segmental Glomerulosclerosis in a Family with Familial Partial Lipodystrophy due to a Mutation in <b><i>LMNA</i></b>

Abstract

<b><i>Background and Aim:</i></b> Focal segmental glomerulosclerosis (FSGS) is a common cause of idiopathic nephrotic syndrome in adults (35%). A number of genetic and familial forms of FSGS have been recognized. Here, we report a large pedigree with a pathogenic mutation in <i>LMNA</i> (R349W) in which four members were found to have biopsy-proven FSGS. The <i>LMNA</i> gene codes for lamins A and C, major components of the nuclear lamina which function in nuclear architecture, integrity and the regulation of gene expression. <b><i>Methods:</i></b> Pedigree screening and mutation analysis of <i>LMNA</i> gene in all family members. Renal biopsies were performed in proteinuric patients. A molecular 3D model of the familial <i>LMNA</i> mutation was constructed. <b><i>Results:</i></b> There were a total of 16 affected members from four generations, 12 of whom were found to carry the germline <i>LMNA</i> mutation. All affected adults had clinical features of familial partial lipodystrophy (FPLD) of the non-Dunnigan variety. Four patients within the same generation presented with a variable degree of renal impairment and proteinuria. Renal biopsies from all four revealed FSGS. The familial mutation is a missense change (R349W) in exon 6 of LMNA (c.1045C>T). <b><i>Conclusions:</i></b> We report a genetic link between <i>LMNA</i> and biopsy-proven FSGS in a large pedigree with FPLD. This unexpected association extends the disease spectrum of <i>LMNA</i> to the kidney and suggests that the physiological role of <i>LMNA</i> could be relevant to the maintenance of glomerular structure and function.