Causes
There are currently several known genetic causes of the hereditary forms of FSGS.
| Gene | OMIM | Description |
|---|---|---|
| FSGS1: ACTN4 | 603278 | The first gene involved with this disorder is ACTN4, which encodes alpha-actinin 4. This protein crosslinks bundles of actin filaments and is present in the podocyte. Mutations in this protein associated with FSGS result in increased affinity for actin binding, formation of intracellular aggregates, and decreased protein half-life. While it is unclear how these effects might lead to FSGS there are a number of theories. Firstly, protein aggregation may have a toxic effect on the podocyte. Secondly, decreased protein half-life or increased affinity for actin binding may alter actin polymerization and thereby affect the podocytes cytoskeletal architecture. |
| FSGS2: TRPC6 | 603965 | A second gene associated with FSGS is TRPC6, which encodes a member of the canonical family of TRP channels. This family of ion channels conduct cations in a largely non-selective manner. As with ACTN4, TRPC6 is expressed in podocytes. While TRP channels can be activated through a variety of methods, TRPC6 is known to be activated by phospholipase C stimulation. There are at least 6 mutations in this channel, located throughout the channel. At least one of these mutations, P112Q, leads to increased intracellular calcium influx. It is unclear how this might lead to FSGS, though it has been proposed that it may result in alteration of podocyte dynamics or podocytopenia. |
| FSGS3: CD2AP | 607832 | Another gene that may be involved in hereditary forms of FSGS is the gene known as CD2AP (CD2 associated protein) or CMS (Cas binding protein with multiple SH3 domains). The protein expressed by this gene is expressed in podocytes where it interacts with fyn and synaptopodin. There is a report that a splicing mutation in this gene was found in two patients with HIV associated FSGS and this led to altered protein translation. This has been theorized to result in altered actin binding and, thus, alteration of the cytoskeletal podocyte architecture. |
| FSGS4: APOL1 | 612551 | In people of African descent, two common variants in APOL1 have been associated with FSGS. It is believed that these variants arose as a defensive mechanism against Trypanosoma brucei rhodesiense or some other sub-Saharan parasite despite conferring high susceptibility to FSGS when inherited from both parents. |
| FSGS5: INF2 | 613237 | Another gene associated with FSGS is INF2, which encodes a member of the formin family of actin-regulating proteins. The observation that alterations in this podocyte-expressed formin cause FSGS emphasizes the importance of fine regulation of actin polymerization in podocyte function. |
| SRN1: NPHS2 | 600995 | Mutations in the NPHS2 gene, which codes for the protein called podocin, can cause focal segmental glomerulosclerosis. This is a recessive form of FSGS. An affected individual has two mutant copies of the NPHS2 gene, in contrast to ACTN4 and TRPC6 mediated forms of disease, which are dominant and require only one mutant copy of the gene. NPHS2-mediated FSGS is resistant to treatment with steroids. |
Read more about this topic: Focal Segmental Glomerulosclerosis