Glomeruli are functional filtration units comprising a capillary network of endothelial cells and mesangial cells, which are separated from podocytes by a basement membrane., Podocyte injury and loss contribute to proteinuria and glomerulosclerosis.,,,,, Numerous podocyte gene products, such as nephrin (NPHS1), podocin (NPHS2), laminin beta-2 (LAMB2),, a-actinin-4 (ACTN4
), Wilms' tumor suppressor gene 1 (WT1), and inverted forming 2 (INF2), are required to construct the podocyte body and foot processes.
Many loci have been identified, including FTO (Hubacek et al., 2012); ACTN4
, TRPC6, INF2, UMOD, MHC, PLA2R1/sPLA2, complement factors, APOL1 (Friedman & Pollak, 2011); and GATM/SPATA5L1 and SHROOM3 (Li, 2015).
Among the dysregulated genes, the top 12 genes from All Sources, Blood Source, Lymphocyte Source, and Monocyte Source were CDC37, NCOA2, P2RY12, RXRB, EDEM2, ACTN4
, STX12, PPM1A, PRKACB, DUSP10, VEGFA, and SLC44A2.
This is particularly of interest given recent work highlighting that single bouts of exercise increase EVs (ACTN4
, ADAM10, ALIX, ANAX11, and CD81) and miRNA to potentially coordinate communication of nutrient homeostasis between muscle, endothelium, as well as liver [66, 67].
North et al., "Mutations in ACTN4
, encoding a-actinin-4, cause familial focal segmental glomerulosclerosis," Nature Genetics, vol.
The mutations in podocyte genes result in either autosomal recessive FSGS (NPHS1, NPHS2, LAMB2, PLCE1, ARGHDIA, MYO1E and other genes) or autosomal dominant FSGS (ACTN4
, CD2AP, INF2, TRPC6, WT1, ARHGAP24 and other genes) or mitochondrial disorders (CoQ6, tRNALeu, tRNATyr, tRNAIle).
(32) The remaining proteins, specifically TPM1, ACTB, ACTN4
, LMNA, and TUBB, are important elements in the formation of the cytoskeleton itself.
Mutational analysis of seven podocyte genes (NPHS1, NPHS2, WT1, CD2AP, ACTN4
, TRPC6 and PLCE1) in 19 non-familial childhood-onset, steroid resistant, biopsy-proven FSGS patients revealed variants of NPHS1, NPHS2, WT1 and CD2AP that could be the cause of the disease in four subjects (21%).
There have been several reports on this disease in family groups, and mutations in the CoQ2 and ACTN4
genes were found to be responsible (2.5).
Genetic factors associated with FSGS include HLA DR4, a mutation of NPHS2 which codes for podocin and a mutation of ACTN4
which codes for actinin, a structural protein found in the podocyte.1 Immune dysregulation is common in FSGS patients and higher IgG/IgM ratios are found in patients who respond to therapy compared with those who do not.
Nephrin, podocin, synaptopodin, podocalyxin, CD2AP, ACTN4
(encodes for [alpha]-actinin 4), PTPRO (encodes for GLEPP-1), and WT1 mRNA have been isolated from urine of patients with varying glomerulopathies.
Short NuMA could bind with alpha–actinin-4 (ACTN4
), a putative tumor promoting gene.