Glomerulopathy With Fibronectin Deposits 2

A number sign (#) is used with this entry because of evidence that glomerulopathy with fibronectin deposits-2 (GFND2) is caused by heterozygous mutation in the gene encoding fibronectin-1 (FN1; 135600) on chromosome 2q35.

Description

Glomerulopathy with fibronectin deposits is a genetically heterogeneous autosomal dominant disorder characterized clinically by proteinuria, microscopic hematuria, and hypertension that leads to end-stage renal failure in the second to fifth decade of life. Pathologic examination shows enlarged glomeruli with mesangial and subendothelial fibrillary deposits that show strong immunoreactivity to fibronectin (Castelletti et al., 2008).

For a discussion of genetic heterogeneity of GFND, see 137950.

Clinical Features

Mazzucco et al. (1992) described an Italian mother and daughter with slowly progressive nephrotic syndrome. Proteinuria was first detected at ages 25 and 11 years, respectively. Renal biopsy from both patients showed similar glomerular changes, including marked widening of the mesangial stalk, irregular thickening of the basement membrane, and presence of mesangial and subendothelial deposits. Electron microscopy disclosed huge glomerular electron-dense deposits containing 12-nm fibrils. Immunohistochemical studies showed strong fibronectin staining in the mesangium and along glomerular basement membranes. Most glomerular fibronectin was plasma-derived, as shown by specific monoclonal antibodies. The mother showed a slow decrease of glomerular function, and a second biopsy performed 8 years after the first investigation showed scarcely modified glomerular changes, consistent with an indolent evolution. In a review of the histologic findings of the mother and daughter reported by Mazzucco et al. (1992), Strom et al. (1995) stated that the deposits were granular in nature with a few 12-nm fibrils in the mesangial and subendothelial spaces. In a follow-up of this family, Castelletti et al. (2008) noted that the 53-year-old mother had moderately reduced renal function and the 25-year-old daughter had normal renal function. A paternal aunt of the mother died at 37 years of nephropathy.

Assmann et al. (1995) reported an affected father and son from the Netherlands. Low-grade proteinuria and hypertension were discovered in the father at age 30 years, and proteinuria in the son at age 18. Renal biopsies from both patients disclosed a distinct form of fibrillary glomerulonephritis that was characterized by massive deposits of a homogeneous eosinophilic material in the mesangial and subendothelial areas. Staining for amyloid was negative, and staining for immunoglobulins was faint. However, the material stained strongly for plasma-derived fibronectin. Electron microscopy showed that the mesangial and subendothelial deposits were composed of irregularly arranged fibrils or microtubules 10 to 12 nm in diameter. In both patients, the disorder showed indolent course with hardly any deterioration of renal function. Assmann et al. (1995) concluded that fibrillary glomerulonephritis with massive deposits of fibronectin represents a rare form of familial glomerulonephritis.

Niimi et al. (2002) reported a 3-year-old Japanese boy with proteinuria, microscopic hematuria, and hypertension. Renal function was intact, but renal biopsy showed enlarged glomeruli with granular fibronectin deposits in the peripheral loop and mesangium. There were no immune deposits and no evidence of systemic disease. Twelve other family members were subsequently found to have mild hematuria or proteinuria, but none were biopsied. Renal function in the proband was preserved during 7 years of follow-up.

Inheritance

Autosomal dominant inheritance of GFND2 was supported in 6 affected families reviewed by Strom et al. (1995). There were affected individuals in 2 generations in 4 of the families, including a father and 4 sons in 1.

Mapping

By linkage analysis of a large Italian family with GFND2 first reported by Strom et al. (1995), Castelletti et al. (2008) found linkage to the FN1 gene on chromosome 2q34 (2-point Z-max = 3.084 for markers D2S128 and D2S2361). Linkage was excluded from the GFND1 locus on 1q32.

Molecular Genetics

In affected individuals from 6 unrelated families with GFND2, Castelletti et al. (2008) identified heterozygous mutations in the FN1 gene (135600.0001-135600.0003). Four of the families had previously been reported by Mazzucco et al. (1992), Strom et al. (1995), Assmann et al. (1995), and Niimi et al. (2002). Although 3 families shared the same mutation, there was no evidence for a founder effect. Six (40%) of 15 affected families were found to have FN1 mutations, suggesting genetic heterogeneity.