title: MAGI2Mutations 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 inmembrane-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. AlthoughMAGI2has been shown to interact with nephrin and regulate podocyte cytoskeleton and slit diaphragm dynamics,MAGI2mutations 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 theMAGI2gene are causal for congenital SRNS.
authors.affiliation: Bristol Renal and Children's Renal Unit, School of Clinical Sciences, University of Bristol, Bristol, United Kingdom.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Bierzynska
authors.affiliation: Division of Transplantation Immunology and Mucosal Biology, Department of Experimental Immunobiology, and.
authors.forename: Katrina
authors.initials: K
authors.lastname: Soderquest
authors.affiliation: Bristol Genetics Laboratory, North Bristol National Health Service Trust, Bristol, United Kingdom; and.
authors.forename: Philip
authors.initials: P
authors.lastname: Dean
authors.affiliation: Bristol Renal and Children's Renal Unit, School of Clinical Sciences, University of Bristol, Bristol, United Kingdom.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Colby
authors.affiliation: Bristol Renal and Children's Renal Unit, School of Clinical Sciences, University of Bristol, Bristol, United Kingdom.
authors.forename: Ruth
authors.initials: R
authors.lastname: Rollason
authors.affiliation: Alder Hey Children's Hospital, Liverpool, United Kingdom.
authors.forename: Caroline
authors.initials: C
authors.lastname: Jones
authors.affiliation: Bristol Renal and Children's Renal Unit, School of Clinical Sciences, University of Bristol, Bristol, United Kingdom.
authors.forename: Carol D
authors.initials: CD
authors.lastname: Inward
authors.affiliation: Bristol Renal and Children's Renal Unit, School of Clinical Sciences, University of Bristol, Bristol, United Kingdom.
authors.forename: Hugh J
authors.initials: HJ
authors.lastname: McCarthy
authors.affiliation: Division of Genetics and Molecular Medicine, Faculty of Life Sciences and Medicine, King's College London, London, United Kingdom.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Simpson
authors.affiliation: Division of Transplantation Immunology and Mucosal Biology, Department of Experimental Immunobiology, and.
authors.forename: Graham M
authors.initials: GM
authors.lastname: Lord
authors.affiliation: Bristol Genetics Laboratory, North Bristol National Health Service Trust, Bristol, United Kingdom; and.
authors.forename: Maggie
authors.initials: M
authors.lastname: Williams
authors.affiliation: Bristol Renal and Children's Renal Unit, School of Clinical Sciences, University of Bristol, Bristol, United Kingdom.
authors.forename: Gavin I
authors.initials: GI
authors.lastname: Welsh
authors.affiliation: Division of Transplantation Immunology and Mucosal Biology, Department of Experimental Immunobiology, and.
authors.forename: Ania B
authors.initials: AB
authors.lastname: Koziell
authors.affiliation: Bristol Renal and Children's Renal Unit, School of Clinical Sciences, University of Bristol, Bristol, United Kingdom; m.saleem@bristol.ac.uk.
authors.forename: Moin A
authors.initials: MA
authors.lastname: Saleem
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins / Q000235:genetics*; D005260:Female; D051528:Guanylate Kinases; D006801:Humans; D007223:Infant; D008297:Male; D009154:Mutation; D009404:Nephrotic Syndrome / Q000151:congenital* / Q000235:genetics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D051528:Guanylate Kinases; C485777:MAGI2 protein, human
keywords: familial nephropathy; genetic renal disease; nephrin; nephrotic syndrome; podocyte; proteinuria