MAGI2/S-SCAM outside brain

Nagashima, Shunta; Kodaka, Manami; Iwasa, Hiroaki; Hata, Yoshinobu

doi:10.1093/jb/mvv009

Cited by 27 publications

(20 citation statements)

References 67 publications

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“…MAGI2 together with its paralogues MAGI1 and MAGI3 belong to the membrane-associated guanylate kinase (MAGUK) family of scaffolding proteins highly expressed in neurones and normally associated with neurological function [17][18][19] . MAGI proteins function as molecular scaffolds coordinating signalling complexes by linking cell surface receptors to the cytoskeleton but differ from other members of the MAGUK family by having a guanylate kinase (GK) domain at the N-terminus as well as WW Aside from published evidence that MAGI2 is a component of the multi-protein complex at the slit diaphragm, MAGI2 deleted mice die soon after birth from podocyte injury, severe proteinuria and end stage renal failure, indicating a profound developmental slit diaphragm defect 17,19,20,22 . Furthermore, MAGI2 is a WT1 target during podocyte development and has been previously implicated in RhoA regulation/signalling known to play a critical role in actin cytoskeletal regulation in podocytes.…”

Section: Discussionmentioning

confidence: 99%

MAGI2 Mutations Cause Congenital Nephrotic Syndrome

Bierżyńska¹,

Soderquest

Dean

et al. 2016

JASN

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Steroid–resistant nephrotic syndrome (SRNS), a heterogeneous disorder of the renal glomerular filtration barrier, results in impairment of glomerular permselectivity. Inheritance of genetic SRNS may be autosomal dominant or recessive, with a subset of autosomal recessive SRNS presenting as congenital nephrotic syndrome (CNS). Mutations in 53 genes are associated with human SRNS, but these mutations explain ≤30% of patients with hereditary cases and only 20% of patients with sporadic cases. The proteins encoded by these genes are expressed in podocytes, and malfunction of these proteins leads to a universal end point of podocyte injury, glomerular filtration barrier disruption, and SRNS. Here, we identified novel disease–causing mutations in membrane–associated guanylate kinase, WW, and PDZ domain–containing 2 (MAGI2) through whole-exome sequencing of a deeply phenotyped cohort of patients with congenital, childhood–onset SRNS. Although MAGI2 has been shown to interact with nephrin and regulate podocyte cytoskeleton and slit diaphragm dynamics, MAGI2 mutations have not been described in human SRNS. We detected two unique frameshift mutations and one duplication in three patients (two families); two siblings shared the same homozygous frameshift mutation, whereas one individual with sporadic SRNS exhibited compound heterozygosity. Two mutations were predicted to introduce premature stop codons, and one was predicted to result in read through of the normal translational termination codon. Immunohistochemistry in kidney sections from these patients revealed that mutations resulted in lack of or diminished podocyte MAGI2 expression. Our data support the finding that mutations in the MAGI2 gene are causal for congenital SRNS.

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Section: Discussionmentioning

confidence: 99%

MAGI2 Mutations Cause Congenital Nephrotic Syndrome

Bierżyńska¹,

Soderquest

Dean

et al. 2016

JASN

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“…First, it is likely that MAGI2 has important functions beyond its interaction with RapGEF2. MAGI2 protein contains multiple protein interacting domains (PDZ and WW) and mediates numerous protein-protein interactions essential for proper podocyte function 2,22,23 . For example, MAGI2 directly interacts with nephrin and forms part of the intricate cytoplasmic protein complex at the slit diaphragm 2,24 .…”

Section: Discussionmentioning

confidence: 99%

Disruption of MAGI2-RapGEF2-Rap1 signaling contributes to podocyte dysfunction in congenital nephrotic syndrome caused by mutations in MAGI2

Zhu

et al. 2019

Kidney International

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“…However, in contrast to the remaining structural domains of MAGI2, no specific binding proteins have been described for the affected PDZ0 domain (available from the authors). 30 Proteinuria is a symptom of NS. Direct proteinuria detection has been established in transgenic zebrafish that express vitamin D-binding protein green fluorescent protein in the serum with quantitation by the green fluorescent protein-enzyme-linked immunosorbent assay in water of = Figure 2 | (continued) observation period.…”

Section: Discussionmentioning

confidence: 99%

Corticosteroid treatment exacerbates nephrotic syndrome in a zebrafish model of magi2a knockout

Jobst-Schwan

Hoogstraten

Kolvenbach

et al. 2019

Kidney International

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Recently, recessive mutations of MAGI2 were identified as a cause of steroid-resistant nephrotic syndrome (SRNS) in humans and mice. To further delineate the pathogenesis of MAGI2 loss of function, we generated stable knockout lines for the two zebrafish orthologues magi2a and magi2b by CRISPR/Cas9. We also developed a novel assay for the direct detection of proteinuria in zebrafish independent of transgenic background. Whereas knockout of magi2b did not yield a nephrotic syndrome phenotype, magi2a -/larvae developed ascites, periorbital edema, and proteinuria, as indicated by increased excretion of low molecular weight protein. Electron microscopy demonstrated extensive podocyte foot process effacement. As in human SRNS, we observed genotype/phenotype correlation, with edema onset occurring earlier in zebrafish with truncating alleles (5-6 days post fertilization) versus hypomorphic alleles (19-20 days post fertilization). Paradoxically, corticosteroid treatment exacerbated the phenotype, with earlier onset of edema. In contrast, treatment with cyclosporine A or tacrolimus had no significant effect. Although RhoA signaling has been implicated as a downstream mediator of MAGI2 activity, targeting of the RhoA pathway did not modify the nephrotic syndrome phenotype. In the first CRISPR/Cas9 zebrafish knockout model of SRNS, we found that corticosteroids may have a paradoxical effect in the setting of specific genetic mutations.

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MAGI2/S-SCAM outside brain

Cited by 27 publications

References 67 publications

MAGI2 Mutations Cause Congenital Nephrotic Syndrome

MAGI2 Mutations Cause Congenital Nephrotic Syndrome

Disruption of MAGI2-RapGEF2-Rap1 signaling contributes to podocyte dysfunction in congenital nephrotic syndrome caused by mutations in MAGI2

Corticosteroid treatment exacerbates nephrotic syndrome in a zebrafish model of magi2a knockout

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