Glomerulopathy With Fibronectin Deposits 1

Description

Glomerulopathy with fibronectin deposits (GFND) 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 (FN1; 135600) (Castelletti et al., 2008).

Genetic Heterogeneity of Glomerulopathy with Fibronectin Deposits

The GFND1 locus maps to chromosome 1q32. See also GFND2 (601894), which is caused by mutation in the FN1 gene (135600) on chromosome 2q35.

Clinical Features

Tuttle et al. (1987) described a father and 4 sons with an unusual lobular glomerulopathy. Electron microscopic examination showed extensive mesangial and subendothelial deposits of amorphous electron-dense material. The 64-year-old father (of 10 children) had asymptomatic proteinuria. He refused a renal biopsy. Four of his sons in their 20s and 30s had hypertension, proteinuria, and hematuria. One had progressive renal failure requiring kidney transplantation at age 18 years, and kidney transplantation was under consideration in a second patient.

Abt et al. (1991) described a similar family. The proband was a white male found to have 2+ proteinuria during a pre-summer camp physical examination at the age of 14 years. Edema and hypertension later developed. The mother had had proteinuria and hypertension diagnosed at the age of 19 during her first pregnancy. During her third pregnancy, at the age of 26, she suffered a massive cerebrovascular accident which resulted in her death. Autopsy revealed what was considered to be membranoproliferative glomerulonephritis. Two brothers of the mother (maternal uncles of the proband) had hypertension, proteinuria, and cerebrovascular accidents from which 1 died at the age of 35. The maternal grandfather had died suddenly following a cerebrovascular accident at the age of 48 years. The glomerulopathy in these cases was characterized by marked lobular accentuation with only a modest increase in mesangial cellularity. Ultrastructural studies showed amorphous granular subendothelial material distending capillary loops and mesangial regions. This material accounted for the pronounced lobular accentuation.

Burgin et al. (1980) reported a kindred in which 2 brothers and a sister had proteinuria and microhematuria. A maternal male first cousin was also affected. Nephropathy was first diagnosed at ages 29, 31, 32, and 42. Renal biopsy of 3 patients and the autopsy specimen of a fourth showed identical glomerular lesions characterized by subendothelial, transmembranous, and mesangial deposition of fibrillary structures visible by electron microscopy. Other features included hypertension and nephrotic syndrome in 2 patients, and otosclerosis in 1. The mother of the 3 affected sibs died of renal failure at age 34, and another brother reportedly had mild proteinuria and microhematuria. No serologic abnormalities were observed and there was no evidence of systemic deposition of the abnormal fibrils.

Strom et al. (1995) reexamined the renal histologic findings in the family reported by Burgin et al. (1980). There were homogeneous PAS-positive deposits in the mesangium and subendothelial space that showed strong immunoreactivity to fibronectin. Electron microscopy of 2 specimens showed confluent areas of fibrils with a diameter of 14 to 16 nm in intramembranous and subepithelial regions. These fibrillary deposits were not consistent with amyloid, and there was no evidence of immunoglobulin deposition.

Gemperle et al. (1996) provided a 15-year follow-up of 157 members of the 5-generation family first reported by Burgin et al. (1980). Albuminuria developed in the third and fourth decades of life and showed slow progression to end-stage renal disease over a period of 15 to 20 years. Related features included generalized distal renal tubular acidosis type IV, hypertension, and the nephrotic syndrome. Younger individuals in the later generations frequently had unexplained microalbuminuria, which may have indicated incipient glomerular disease. Electron microscopy showed that the glomerular deposits consisted of randomly oriented fibrils that were immunoreactive to fibronectin. One affected male and his unaffected sister were found to have renal cell carcinoma. The disease relapsed in one renal transplant, raising the possibility of the presence of a circulating or transferable factor that could be part of the deposited fibrillar material, or alternatively, interfere with the glomerular handling of the deposited material.

Sato et al. (1998) reported what they considered to be the first Asian case in a 23-year-old Japanese man with lobular glomerulopathy characterized by mesangial and subendothelial expansion with numerous PAS-positive deposits. Electron microscopy showed massive fine granular deposits with a homogeneous distribution. Immunohistochemistry showed positive staining of fibronectin, as well as IgG and fibrinogen, in the mesangium and capillary loop. Family history revealed that the patient's grandfather, 2 aunts, and a cousin on his father's side had developed end-stage renal failure.

Mapping

In the large kindred reported by Burgin et al. (1980) and Gemperle et al. (1996), Vollmer et al. (1998) found linkage of the disorder (GFND1) to chromosome 1q32 (maximum 2-point lod score of 4.17 at marker D1S249 and a maximum multipoint lod score of 4.41 at D1S2782). Haplotype analysis delineated a 4.1-cM candidate region between D1S2872 and D1S2891.

Inheritance

In the family with glomerulopathy with fibronectin deposits reported by Burgin et al. (1980), the inheritance pattern was autosomal dominant.

Molecular Genetics

Exclusion of Candidate Genes

By haplotype analysis with microsatellite markers spanning an interval of more than 56 cM on chromosome 2q34, Hildebrandt et al. (1996) excluded the fibronectin, villin (VIL; 193040), and desmin (DES; 125660) genes as being involved in the GFND1 family reported by Burgin et al. (1980).

In affected members of the family reported by Burgin et al. (1980), Vollmer et al. (1998) excluded mutations in the uteroglobin gene (UGB; 192020).

By cloning and analyzing the GFND1 critical region on 1q32, Vollmer et al. (2000) excluded mutations in genes that are regulators of complement activation in patients from the large kindred reported by Burgin et al. (1980). For example, no mutations were identified in the complement receptor-2 gene (CR2; 120650), the membrane cofactor protein gene (MCP; 120920), or the decay accelerating factor gene (DAF; 125240).

Animal Model

The observation by Gemperle et al. (1996) of relapse in a renal transplant was of interest in light of the findings of Zhang et al. (1997) that mice in which the uteroglobin gene had been disrupted developed severe fibronectin-deposit renal glomerular disease. The deposition consisted predominantly of multimeric fibronectin. The molecular mechanism that normally prevents fibronectin deposition appears to involve high-affinity binding of uteroglobin with fibronectin to form heteromers that counteract fibronectin self-aggregation, which is required for abnormal tissue deposition. These observations suggested that a defect involving uteroglobin may underlie some cases of familial glomerular nephritis with fibronectin deposition.