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MAGI2 Mutations Cause Congenital Nephrotic Syndrome

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MAGI2 Mutations Cause Congenital Nephrotic Syndrome. / Bierzynska, Agnieszka; Soderquest, Katrina; Dean, Philip; Colby, Elizabeth; Rollason, Ruth; Jones, Caroline; Inward, Carol; McCarthy, Hugh; Simpson, Michael A; Lord, Graham M.; Williams, Maggie; Welsh, Gavin; Koziell, Ania; Saleem, Moin.

In: Journal of the American Society of Nephrology, Vol. 28, No. 5, 05.2017, p. 1614-1621.

Research output: Contribution to journalArticle

Harvard

Bierzynska, A, Soderquest, K, Dean, P, Colby, E, Rollason, R, Jones, C, Inward, C, McCarthy, H, Simpson, MA, Lord, GM, Williams, M, Welsh, G, Koziell, A & Saleem, M 2017, 'MAGI2 Mutations Cause Congenital Nephrotic Syndrome', Journal of the American Society of Nephrology, vol. 28, no. 5, pp. 1614-1621. https://doi.org/10.1681/ASN.2016040387

APA

Bierzynska, A., Soderquest, K., Dean, P., Colby, E., Rollason, R., Jones, C., ... Saleem, M. (2017). MAGI2 Mutations Cause Congenital Nephrotic Syndrome. Journal of the American Society of Nephrology, 28(5), 1614-1621. https://doi.org/10.1681/ASN.2016040387

Vancouver

Bierzynska A, Soderquest K, Dean P, Colby E, Rollason R, Jones C et al. MAGI2 Mutations Cause Congenital Nephrotic Syndrome. Journal of the American Society of Nephrology. 2017 May;28(5):1614-1621. https://doi.org/10.1681/ASN.2016040387

Author

Bierzynska, Agnieszka ; Soderquest, Katrina ; Dean, Philip ; Colby, Elizabeth ; Rollason, Ruth ; Jones, Caroline ; Inward, Carol ; McCarthy, Hugh ; Simpson, Michael A ; Lord, Graham M. ; Williams, Maggie ; Welsh, Gavin ; Koziell, Ania ; Saleem, Moin. / MAGI2 Mutations Cause Congenital Nephrotic Syndrome. In: Journal of the American Society of Nephrology. 2017 ; Vol. 28, No. 5. pp. 1614-1621.

Bibtex

@article{7cef385e33c44af0aa5f8112ecc1fe55,
title = "MAGI2 Mutations Cause Congenital Nephrotic Syndrome",
abstract = "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.",
keywords = "Podocyte, Genetic renal disease, Nephrin, Familial nephropathy, Proteinuria, Nephrotic Syndrome",
author = "Agnieszka Bierzynska and Katrina Soderquest and Philip Dean and Elizabeth Colby and Ruth Rollason and Caroline Jones and Carol Inward and Hugh McCarthy and Simpson, {Michael A} and Lord, {Graham M.} and Maggie Williams and Gavin Welsh and Ania Koziell and Moin Saleem",
year = "2017",
month = "5",
doi = "10.1681/ASN.2016040387",
language = "English",
volume = "28",
pages = "1614--1621",
journal = "Journal of the American Society of Nephrology",
issn = "1046-6673",
publisher = "Lippincott Williams and Wilkins",
number = "5",

}

RIS - suitable for import to EndNote

TY - JOUR

T1 - MAGI2 Mutations Cause Congenital Nephrotic Syndrome

AU - Bierzynska, Agnieszka

AU - Soderquest, Katrina

AU - Dean, Philip

AU - Colby, Elizabeth

AU - Rollason, Ruth

AU - Jones, Caroline

AU - Inward, Carol

AU - McCarthy, Hugh

AU - Simpson, Michael A

AU - Lord, Graham M.

AU - Williams, Maggie

AU - Welsh, Gavin

AU - Koziell, Ania

AU - Saleem, Moin

PY - 2017/5

Y1 - 2017/5

N2 - 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.

AB - 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.

KW - Podocyte

KW - Genetic renal disease

KW - Nephrin

KW - Familial nephropathy

KW - Proteinuria

KW - Nephrotic Syndrome

U2 - 10.1681/ASN.2016040387

DO - 10.1681/ASN.2016040387

M3 - Article

C2 - 27932480

VL - 28

SP - 1614

EP - 1621

JO - Journal of the American Society of Nephrology

JF - Journal of the American Society of Nephrology

SN - 1046-6673

IS - 5

ER -