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MAGI2 Mutations Cause Congenital Nephrotic Syndrome

Research output: Contribution to journalArticle

Original languageEnglish
Pages (from-to)1614-1621
Number of pages8
JournalJournal of the American Society of Nephrology
Issue number5
Early online date8 Dec 2016
DateAccepted/In press - 9 Oct 2016
DateE-pub ahead of print - 8 Dec 2016
DatePublished (current) - May 2017


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.

    Research areas

  • Podocyte, Genetic renal disease, Nephrin, Familial nephropathy, Proteinuria, Nephrotic Syndrome

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    Rights statement: This is the author accepted manuscript (AAM). The final published version (version of record) is available online via American Society of Nephrology at . Please refer to any applicable terms of use of the publisher.

    Accepted author manuscript, 491 KB, PDF document


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