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2017 ; 28
(5
): 1614-1621
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MAGI2 Mutations Cause Congenital Nephrotic Syndrome
#MMPMID27932480
Bierzynska A
; Soderquest K
; Dean P
; Colby E
; Rollason R
; Jones C
; Inward CD
; McCarthy HJ
; Simpson MA
; Lord GM
; Williams M
; Welsh GI
; Koziell AB
; Saleem MA
J Am Soc Nephrol
2017[May]; 28
(5
): 1614-1621
PMID27932480
show ga
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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