Mutations in ACTN4, encoding α-actinin-4, cause familial focal segmental glomerulosclerosis

Kaplan, Joshua M.; Kim, Sung-Han; North, Klaus; Rennke, Helmut G.; Correia, Lori Ann; Tong, Hui Qi; Mathis, Beverly J.; Rodríguez‐Pérez, José Carlos; Allen, Philip G.; Beggs, Alan H.; Pollak, Martin R.

doi:10.1038/73456

Cited by 1,133 publications

(904 citation statements)

References 20 publications

Supporting

Mentioning

862

Contrasting

Unclassified

Order By: Relevance

“…In conclusion, the tight developmental and tissue‐specific regulation of MXE expression suggests that changes in MXE function or expression might cause aberrant development and human disease (Xiong et al , 2015). Pathogenic mutations in MXEs are known to cause Timothy syndrome, cardiomyopathy, cancer and kidney disease (Kaplan et al , 2000; Splawski et al , 2004, 2005; David et al , 2010; Mayr et al , 2011). …”

Section: Resultsmentioning

confidence: 99%

The landscape of human mutually exclusive splicing

Hatje

Rahman

Vidal

et al. 2017

Molecular Systems Biology

View full text Add to dashboard Cite

Mutually exclusive splicing of exons is a mechanism of functional gene and protein diversification with pivotal roles in organismal development and diseases such as Timothy syndrome, cardiomyopathy and cancer in humans. In order to obtain a first genomewide estimate of the extent and biological role of mutually exclusive splicing in humans, we predicted and subsequently validated mutually exclusive exons (MXEs) using 515 publically available RNA‐Seq datasets. Here, we provide evidence for the expression of over 855 MXEs, 42% of which represent novel exons, increasing the annotated human mutually exclusive exome more than fivefold. The data provide strong evidence for the existence of large and multi‐cluster MXEs in higher vertebrates and offer new insights into MXE evolution. More than 82% of the MXE clusters are conserved in mammals, and five clusters have homologous clusters in Drosophila. Finally, MXEs are significantly enriched in pathogenic mutations and their spatio‐temporal expression might predict human disease pathology.

show abstract

Section: Resultsmentioning

confidence: 99%

The landscape of human mutually exclusive splicing

Hatje

Rahman

Vidal

et al. 2017

Molecular Systems Biology

View full text Add to dashboard Cite

show abstract

“…Mutations in the gene encoding α-actinin-4 ( ACTN4 ) cause a late-onset autosomal dominant form of FSGS [31]. Mice with podocyte-specific expression of a high-affinity variant of α -actinin-4 [32] or genetic deletion of α -actinin-4 [33] or expressing ACTN4 gene harboring a disease-associated mutation are characterized by proteinuria with globally disrupted podocyte morphology in old mice [33].…”

Section: The Podocyte’s Strength and Weakness: Its Actin Cytoskeletonmentioning

confidence: 99%

Podocyte Mitosis – A Catastrophe

Lasagni

Lazzeri²,

Shankland

et al. 2012

CMM

View full text Add to dashboard Cite

Podocyte loss plays a key role in the progression of glomerular disorders towards glomerulosclerosis and chronic kidney disease. Podocytes form unique cytoplasmic extensions, foot processes, which attach to the outer surface of the glomerular basement membrane and interdigitate with neighboring podocytes to form the slit diaphragm. Maintaining these sophisticated structural elements requires an intricate actin cytoskeleton. Genetic, mechanic, and immunologic or toxic forms of podocyte injury can cause podocyte loss, which causes glomerular filtration barrier dysfunction, leading to proteinuria. Cell migration and cell division are two processes that require a rearrangement of the actin cytoskeleton; this rearrangement would disrupt the podocyte foot processes, therefore, podocytes have a limited capacity to divide or migrate. Indeed, all cells need to rearrange their actin cytoskeleton to assemble a correct mitotic spindle and to complete mitosis. Podocytes, even when being forced to bypass cell cycle checkpoints to initiate DNA synthesis and chromosome segregation, cannot complete cytokinesis efficiently and thus usually generate aneuploid podocytes. Such aneuploid podocytes rapidly detach and die, a process referred to as mitotic catastrophe. Thus, detached or dead podocytes cannot be adequately replaced by the proliferation of adjacent podocytes. However, even glomerular disorders with severe podocyte injury can undergo regression and remission, suggesting alternative mechanisms to compensate for podocyte loss, such as podocyte hypertrophy or podocyte regeneration from resident renal progenitor cells. Together, mitosis of the terminally differentiated podocyte rather accelerates podocyte loss and therefore glomerulosclerosis. Finding ways to enhance podocyte regeneration from other sources remains a challenge goal to improve the treatment of chronic kidney disease in the future.

show abstract

“…10,29 Other primary antibodies used were anti-E-cadherin (clone NCH-38, 1:100, Dako, Glostrup, Denmark) and anti-b-catenin (rabbit polyclonal, ready-to-use, Lab Vision).…”

Section: Tma and Immunohistochemistry (Ihc)mentioning

confidence: 99%

Actinin-4 expression in ovarian cancer: a novel prognostic indicator independent of clinical stage and histological type

Yamamoto

Tsuda

Honda³

et al. 2007

Modern Pathology

View full text Add to dashboard Cite

Actinin-4 is an isoform of non-muscular a-actinin and actin-bundling protein. By enhancing cell motility, actinin-4 shows different biological properties from another isoform of non-muscular actinin 'actinin-1' and variable clinicopathological implications of actinin-4 have been demonstrated in some human malignancies such as breast cancers, lung cancers, and colorectal cancers. We herein described the clinicopathological and prognostic significance of actinin-4 expression in ovarian cancers. Actinin-4 expression was analyzed immunohistochemically in 265 primary ovarian carcinomas: 116 serous, 71 clear cell, 43 endometrioid, and 35 mucinous adenocarcinomas. With reference to endothelial immunoreactivity, cytoplasmic expression of actinin-4 was classified as either low (including negative) or high. Then, various parameters such as patients' characteristics, histopathological findings including E-cadherin and b-catenin immunoreactivity, and clinical outcome, were compared between groups showing differences in the intensity or intracellular distribution of actinin-4 immunoreactivity. High expression of actinin-4 was demonstrated in 137 (57%) cases and was associated with serous histology (P ¼ 0.0075), high histological grade (Po0.0001), an advanced disease stage (P ¼ 0.036), a high degree of residual disease after initial surgery (P ¼ 0.0047), poor patient outcome (5-year survival: 52.4% in the high-expression group vs 71.9% in the low expression group, P ¼ 0.0043 by log-rank test), and also with reduced E-cadherin and preserved b-catenin expressions (P ¼ 0.0097 and 0.017, respectively). Nuclear immunoreactivity for actinin-4 was detected in 20 (7.5%) cases and was associated with low histological grade (P ¼ 0.0079) but not with other variables. Multivariate analysis showed that high actinin-4 expression was an independent prognostic factor for overall survival, as well as a high degree of residual disease and clear-cell histology. Accumulation of actinin-4 in the cytoplasm may be related to a higher propensity for tumor invasiveness and metastasis, probably by enhancing cell motility, and could be a novel prognostic indicator for patients with ovarian carcinomas.

show abstract

Mutations in ACTN4, encoding α-actinin-4, cause familial focal segmental glomerulosclerosis

Cited by 1,133 publications

References 20 publications

The landscape of human mutually exclusive splicing

The landscape of human mutually exclusive splicing

Podocyte Mitosis – A Catastrophe

Actinin-4 expression in ovarian cancer: a novel prognostic indicator independent of clinical stage and histological type

Contact Info

Product

Resources

About