MAGI2 Mutations Cause Congenital Nephrotic Syndrome
| Autor: | P. Dean, Graham M. Lord, Caroline Jones, Carol Inward, Gavin I. Welsh, Ania Koziell, Moin A. Saleem, Maggie Williams, Hugh J. McCarthy, Ruth Rollason, Katrina Soderquest, Michael A. Simpson, Elizabeth Colby, Agnieszka Bierzynska |
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| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Nephrotic Syndrome Translational termination 030232 urology & nephrology Podocyte Compound heterozygosity Frameshift mutation Nephrin 03 medical and health sciences 0302 clinical medicine Clinical Research medicine Congenital nephrotic syndrome Genetics biology Familial nephropathy Genetic renal disease General Medicine medicine.disease Stop codon Proteinuria 030104 developmental biology medicine.anatomical_structure Nephrology Slit diaphragm biology.protein |
| Zdroj: | Bierzynska, A, Soderquest, K, Dean, P, Colby, E, Rollason, R, Jones, C, Inward, C, McCarthy, H, Simpson, M A, Lord, G M, 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 Bierzynska, A, Soderquest, K, Dean, P, Colby, E, Rollason, R, Jones, C, Inward, C D, McCarthy, H J, Simpson, M A, Lord, G M, Williams, M, Welsh, G I, Koziell, A B & Saleem, M A 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 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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