Molecular genetic analysis of steroid resistant nephrotic syndrome: Detection of a novel mutation.

Background: Nephrotic syndrome is a disorder of the
glomerular filtration barrier, a highly specialized trilayer
structure with unique functional properties.
Recent advances emanating from the field of
molecular genetics have revealed the podocyte as
probably the central player in the control of glomerular
filtration. More specifically, the cell–cell junction
between adjacent podocyte foot processes, namely, the
slit diaphragm, has been revealed to be made up of a
sophisticated multi-protein complex which
dynamically controls foot process architecture via
signaling to the actin cytoskeleton. Nephrotic
Syndrome (NS) is one of the most common idiopathic
primary diseases in childhood. Which is defined as
presence of four main symptoms: proteinuria,
hyperlipidemia, hypoalbuminemia and edema.
According to the patient’s response to the steroid
therapy the disease divided into: resistant and sensitive
groups. About 90% of patients are responsive to
steroid therapy during four weeks who called steroid
sensitive nephrotic syndrome (SSNS). Patients in
whom proteinuria does not stop after about one month
are classified as resistant which describe as steroid
resistant nephrotic syndrome (SRNS).SRNS is
considered as a poor prognostic disease, in which 30-
40% of it progresses to end stage renal disease
(ESRD), requiring dialysis and transplantation. The
most frequent renal histological feature associated with
SRNS is focal segmental glomerulosclerosis (FSGS).
Moreover minimal change nephrotic syndrome
(MCNS), and diffuse mesangial sclerosis (DMS) have
been identified. Genetic forms of SRNS are classified
as isolated kidney disease or syndromic disorder. The
fenestrated endothelium, the glomerular basement
membrane (GBM) and the podocytes form three layers
of glomerular filtration barrier (GFB) which is
impaired in NS and cause proteinuria.
2major proteins of podocytes including nephrin and
podocin, coded by NPHS1 and NPHS2, are considered
to play an important role in GFB. Mutations in these
genes result in altering conformation and stability of
podocytes and causing proteinuria and SRNS. Most
cases of SRNS are considered as sporadic representing
both AR and AD inheritance. NPHS1 and NPHS2
genes are the most common identified genes in AR
This study was aimed to screen mutations causing
disease within NPHS1 and NPHS2, figuring out the
most common mutations in Iranian children and
comprising the prevalence of such mutations among
different nations. Due to heterogeneity of this disease,
This work is partly presented at 5th World Heart and Brain Conference September 24-26, 2018 Abu Dhabi, UAE
Extended Abstract
Vol. 5, Iss.3
Insights in Blood Pressure
WES was performed for 10 patients in pilot study to
evaluate other related genes and exploring new
potential mutations. Indeed, preventing of ineffective
treatment with steroids and helping proper clinician
prediction in post transplantation outcome may be
facilitated via indicating the specific mutations.
Nephrotic syndrome is one of the most common
kidney diseases in childhood. About 20% of children
are steroid-resistant NS (SRNS) which progress to
end-stage renal disease (ESRD). More than 53 genes
are associated with SRNS which represent the genetic
heterogeneity of SRNS. This study was aimed to
screen disease causing mutations within NPHS1 and
NPHS2 and evaluate new potential variants in other
Method: In first phase of study, 25 patients with
SRNS were analyzed for NPHS1 (exon 2, 26) and all
exons of NPHS2 genes by Sanger sequencing. In the
second phase, whole exome sequencing was performed
on 10 patients with no mutations in NPHS1 and
Result: WES analysis revealed a novel mutation in
FAT1 (c.10570C>A; Q3524K). We identified 4
pathogenic mutations, located in exon 4 and 5 of
NPHS2 gene in 20% of patients (V180M, P118L,
R168C and Leu156Phe). Also our study has
contributed to the descriptions of previously known
pathogenic mutations across WT1 (R205C) and
SMARCAL1 (R764Q) and a novel polymorphism in
Conclusion:In summary, this is the first and largest
study among Iranian population with different ethnic
origins that investigates causative variants associated
with SRNS through screening both common genes
(NPHS1 and NPHS2) and whole exome study. Among
25 patients who underwent for PCR sequencing for all
exons of NPHS2, 5 patients carried a mutation causing
disease, suggesting that NPHS2 especially exons 4 and
5 of this gene should be considered as the first step
genetic approach in children with SRNS. For the first
time in this country, 3 known variant were detected in
WT1, SMARCAL1 and CRB2, significantly a novel
variant were identified in FAT1 gene.Our study
concludes that mutations of exon 4 and 5 NPHS2 gene
are common in Iranian and some other ethnic groups.
We suggest conducting WES after NPHS2 screening
and further comprehensive studies to identify the most
common genes in the development of SRNS, which
might help in clinical impact on management in
patients with SRNS.
Because of the heterogeneous clinical and pathological
spectrum, a molecular diagnosis based on sequencing
is required. Identification of mutations causing SRNS
is of importance, not only for therapeutic
considerations but also for genetic counseling.



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