Focal Segmental Glomerulosclerosis 1

A number sign (#) is used with this entry because of evidence that this form of progressive renal disease, referred to here as focal segmental glomerulosclerosis-1 (FSGS1), is caused by heterozygous mutation in the gene encoding alpha-actinin-4 (ACTN4; 604638) on chromosome 19q13.

Description

Focal segmental glomerulosclerosis (FSGS) is a pathologic finding in several renal disorders that manifest clinically as proteinuria and progressive decline in renal function. Some patients with FSGS develop the clinical entity called 'nephrotic syndrome' (see NPHS1; 256300), which includes massive proteinuria, hypoalbuminemia, hyperlipidemia, and edema. However, patients with FSGS may have proteinuria in the nephrotic range without other features of the nephrotic syndrome (summary by D'Agati et al., 2004; Mathis et al., 1998).

D'Agati et al. (2011) provided a detailed review of FSGS, emphasizing that the disorder results from defects of the podocyte.

Because of confusion in the literature regarding use of the terms 'nephrotic syndrome' and 'focal segmental glomerulosclerosis' (see NOMENCLATURE section), these disorders in OMIM are classified as NPHS or FSGS according to how they were first designated in the literature.

Genetic Heterogeneity of Focal Segmental Glomerulosclerosis and Nephrotic Syndrome

Focal segmental glomerulosclerosis and nephrotic syndrome are genetically heterogeneous disorders representing a spectrum of hereditary renal diseases. See also FSGS2 (603965), caused by mutation in the TRPC6 gene (603652); FSGS3 (607832), associated with variation in the CD2AP gene (604241); FSGS4 (612551), mapped to chromosome 22q12; FSGS5 (613237), caused by mutation in the INF2 gene (610982); FSGS6 (614131), caused by mutation in the MYO1E gene (601479); FSGS7 (616002), caused by mutation in the PAX2 gene (167409); FSGS8 (616032), caused by mutation in the ANLN gene (616027); and FSGS9 (616220), caused by mutation in the CRB2 gene (609720).

See also NPHS1 (256300), caused by mutation in the NPHS1 gene (602716); NPHS2 (600995), caused by mutation in the podocin gene (604766); NPHS3 (610725), caused by mutation in the PLCE1 gene (608414); and NPHS4 (256370), caused by mutation in the WT1 gene (607102).

Clinical Features

Mathis et al. (1992) reported a large family with variable expression of a glomerular disease associated with asymptomatic proteinuria and normal renal function (7 patients) or significant proteinuria leading to progressive renal failure (11 patients). Histopathologic changes were variable, but included focal segmental glomerulosclerosis and diffuse glomerulosclerosis. Renal failure usually occurred in the fifth decade of life. The most consistent clinical finding was proteinuria without microscopic hematuria or other significant urinary sediment elements. This disease differed from Alport syndrome (301050) and congenital nephrotic syndrome (256300) in age of onset, urinary findings, and lack of associated conditions, such as deafness.

Mathis et al. (1998) provided follow-up of the family reported by Mathis et al. (1992). An individual was considered affected if he/she had (1) renal biopsy evidence of FSGS; (2) end-stage renal disease without another cause; or (3) elevated urine microalbumin excretion without another cause. The authors noted that emphasized the great variability in the phenotypic expression of the disease gene. They further stated that 'although we have termed the pathologic condition in this family inherited FSGS, this may be misleading,' since some family members developed end-stage renal failure at a relatively young age, whereas others showed only microalbuminuria, including 1 individual whose 2 daughters were severely affected.

Bartram et al. (2016) reported a 13-year-old German girl who presented with arterial hypertension, ocular pain, and nausea. She had pleural effusions and moderate ascites associated with end-stage renal failure; laboratory studies showed renal anemia and proteinuria. Her kidneys were small and hyperechoic with reduced corticomedullary differentiation on ultrasound. She underwent renal transplantation from her father.

Inheritance

The genetic contribution to FSGS etiology is indicated by reports of its occurrence in multiple members of families (Conlon et al., 1995; Faubert and Porush, 1997). Both autosomal dominant and recessive patterns of inheritance have been proposed (Conlon et al., 1995).

The inheritance pattern in the family reported by Mathis et al. (1998) was autosomal dominant with reduced penetrance and variable expressivity.

Pathogenesis

D'Agati et al. (2004) proposed a pathologic classification of FSGS, defining 5 morphologic variants based entirely on assessment of glomerular light microscopic alterations: collapsing variant, tip variant, cellular variant, perihilar variant, and 'not otherwise specified,' with classification into a given category requiring that all preceding categories, as listed, be excluded.

D'Agati et al. (2011) reviewed the pathogenesis of FSGS, with emphasis on loss of the glomerular filtration barrier due to defects in the podocyte.

Mapping

In a large kindred with affected members in at least 5 generations, Mathis et al. (1998) performed linkage analysis and demonstrated mapping to chromosome 19q13; maximum 2-point lod score = 12.28. They narrowed the critical region to approximately 7 cM.

Molecular Genetics

In 3 families with clear evidence of autosomal dominant inheritance of FSGS, including the family reported by Mathis et al. (1992, 1998), Kaplan et al. (2000) identified heterozygous mutations in the ACTN4 gene (604638.0001-604638.0003). They also analyzed the NPHS1 gene (602716) and found no mutations associated with this disorder.

In a 13-year-old German girl with FSGS1, Bartram et al. (2016) identified a de novo heterozygous missense mutation in the ACTN4 gene (G195D; 604638.0004). The mutation was found by gene panel analysis and confirmed by Sanger sequencing. Introduction of the mutation into podocytes showed that the mutant protein had altered localization compared to wildtype and formed multiple F-actin-positive aggregates. Renal epithelial cells derived from the patient and transfected HEK293 cells showed reduced expression of the ACTN4 protein, resulting from increased ubiquitination and subsequent clearance of the mutant protein. Proteomic analysis of patient cells showed disturbances in the ACTN4 interactome with dysregulation of LIM domain proteins, which are important modular regulators of cell adhesion.

Associations Pending Confirmation

See 300319.0001 for discussion of a possible association of FSGS with mutation in the NXF5 gene.

See 300776.0003 for discussion of a possible association of FSGS with mutation in the ALG13 gene.

See 610586.0001 for discussion of a possible association of FSGS with mutation in the ARHGAP24 gene.

Nomenclature

In the literature, use of the clinical term 'nephrotic syndrome' (NPHS) and the pathologic term 'focal segmental glomerulosclerosis' (FSGS) to refer to the same disease entity has generated confusion in the naming and classification of similar disorders. In OMIM, these disorders are classified as NPHS or FSGS according to how they were first designated in the literature. It is important to recognize that FSGS is a histologic pattern of renal injury: some patients with FSGS on biopsy have nephrotic syndrome, whereas others have only mild proteinuria. NPHS and FSGS represent a spectrum of hereditary renal diseases of the podocyte (see reviews by Pollak, 2002; Meyrier, 2005; Caridi et al., 2010; Hildebrandt, 2010).