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

Abstract

Background and Aim: 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 LMNA (R349W) in which four members were found to have biopsy-proven FSGS. The LMNA 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. Methods: Pedigree screening and mutation analysis of LMNA gene in all family members. Renal biopsies were performed in proteinuric patients. A molecular 3D model of the familial LMNA mutation was constructed. Results: There were a total of 16 affected members from four generations, 12 of whom were found to carry the germline LMNA 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). Conclusions: We report a genetic link between LMNA and biopsy-proven FSGS in a large pedigree with FPLD. This unexpected association extends the disease spectrum of LMNA to the kidney and suggests that the physiological role of LMNA could be relevant to the maintenance of glomerular structure and function.

Spectrum of disease associated with partial lipodystrophy: lessons from a trial cohort

“…There have been two other published instances of this mutation, one in a male patient with similar fat distribution, but without the exaggerated dorsocervical fat pad, diabetes, or other features described here . In addition, a large kindred with focal segmental glomerulosclerosis and proteinuria in association with PL has been reported …”

Familial partial lipodystrophy and proteinuric renal disease due to a missense c.1045C > T LMNA mutation

“…The underlying mechanisms are unclear, but hypocomplementemia and elevated C3 nephritic factor, an IgG autoantibody that causes C3 consumption and possibly adipocyte lysis, have been hypothesized as contributing factors (21, 22, 23). However, the presence of proteinuric nephropathy in patients with congenital lipodystrophy due to LMNA mutations has very rarely been reported (6, 7, 8, 9). All patients suffered from FPLD (of the Dunnigan and non-Dunnigan varieties) due to LMNA missense mutations c.1930C > T (p.R644C), c.1444C > T (p.R482W), c.1445G > A (p.R482Q) and c.1045C > T (p.R349W).…”

“…On the other hand, an association between familial partial lipodystrophy (FPLD) and renal disease has been documented in very few cases (6, 7, 8, 9). …”

Biallelic Mutations in Nuclear Pore Complex Subunit NUP107 Cause Early-Childhood-Onset Steroid-Resistant Nephrotic Syndrome

“…A direct link between NUP107 and renal disease has never been shown, but NUP107 knockdown in HeLa cells altered the localization of ELYS, and this affected the proper localization of lamin A/C, 19 an alteration in which caused FSGS. 40 Effect of the Common NUP107 p.Asp831Ala Substitution on the Structure of the Protein and Its Binding to NUP133 To evaluate the effect of p.Asp157Tyr and p.Asp831Ala substitutions from a structural viewpoint, we mapped the variant positions on the crystal structure of the yeast Sec13-Nup145C-Nup84 complex (PDB: 3IKO), 41 which is analogous to the human SEC13-NUP96-NUP107 complex (NUP96 is the C-terminal half product of NUP98 [GenBank: NM_016320.4; MIM: 601021], processed after translation 42,43 ) and the human NUP107-NUP133 complex (PDB: 3CQC). 14 Asp157 is predicted to reside on the surface of the protein, suggesting that the p.Asp157Tyr substitution does not affect the folded structure of NUP107 ( Figure S11).…”