Disease relevance of Actn4

• Hypoxia inactivates inducible nitric oxide synthase in mouse macrophages by disrupting its interaction with alpha-actinin 4 [1].
• Moreover, alpha-actinin 4 and a splice variant of alpha-actinin 1 were both expressed at significantly higher levels (mRNA and protein) in MCs from the lupus prone MRL-lpr/lpr strain [2].
• Alpha-actinin-4-mediated FSGS: an inherited kidney disease caused by an aggregated and rapidly degraded cytoskeletal protein [3].
• Mice deficient in alpha-actinin-4 develop a recessive phenotype characterized by kidney failure, proteinuria, glomerulosclerosis, and retraction of glomerular podocyte foot processes [4].
• Glomerulosclerosis was a relatively late event, accompanied by severe albuminuria and loss of WT1, nephrin, CD2AP, and alpha-actinin-4 [5].

High impact information on Actn4

• In addition, these genetic studies demonstrate that the nonsarcomeric alpha-actinin-4 is involved in the regulation of cell movement [6].
• Cell motility, as measured by lymphocyte chemotaxis assays, was increased in the absence of alpha-actinin-4 [6].
• Therefore, ILK plays an essential role in specifying nephrin and alpha-actinin-4 distribution and in maintaining the slit diaphragm integrity and podocyte architecture [7].
• Co-immunoprecipitation demonstrated that ILK physically interacted with nephrin to form a ternary complex, and alpha-actinin-4 participated in ILK/nephrin complex formation [7].
• During the calcium switch, there were reversible changes in localization and detergent solubility of the slit diaphragm protein ZO-1 and alpha-actinin-4, whereas nephrin and podocin solubility were unchanged [8].

Biological context of Actn4

• Comparison of the phenotype in wild-type, heterozygous, and homozygous Actn4 "knockin" and "knockout" mice, together with our in vitro data, suggests that the phenotypes in mice and humans involve both gain-of-function and loss-of-function mechanisms [3].
• We developed a "knockin" mouse model by replacing Actn4 with a copy of the gene bearing an FSGS-associated point mutation [3].
• Immunofluorescence staining, double-immunolabeling, confocal microscopy, semiquantitative reverse transcription polymerase chain reaction (RT-PCR), and Western blotting were used to detect the distribution and expression of podocin, nephrin, alpha-actinin-4, and glyseraldehyde-3-phosphate dehydrogenase (GAPDH)/beta-actin [9].
• In this study, to investigate the molecular interactions among podocin, nephrin, and alpha-actinin-4, we reconstructed the RNA interference (RNAi) expression vector, pSilencer 2.1-U6, specifically targeting podocin mRNA, and it was transfected into the mouse podocyte clone (MPC5) [9].

Anatomical context of Actn4

• Confocal immunofluorescence microscopy indicated that, while wild-type (WT) alpha-actinin-4 stains into actin cytoskeleton and cell surface ruffles, the mutated protein is only dispersed in the cytoplasm of the lung carcinoma cells [10].
• Conversely, K256E alpha-actinin-4 was detected predominantly in the Triton-insoluble fraction, was excluded from cortical actin, and localized almost exclusively along stress fibers [11].

Associations of Actn4 with chemical compounds

• To better study its progression, a transgenic mouse model was developed by expressing murine alpha-actinin-4 containing a mutation analogous to that affecting a human FSGS family in a podocyte-specific manner using the murine nephrin promoter [12].

Analytical, diagnostic and therapeutic context of Actn4

• Immunofluorescence confirmed podocyte-specific expression of mutant alpha-actinin-4, and real-time RT-PCR revealed that HA-ACTN4 mRNA levels were higher in proteinuric versus non-proteinuric ACTN4-mutant mice [12].
• Video microscopy showed the mutant alpha-actinin-4 to be markedly less dynamic than the wild-type protein [3].

References