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Y. Frishberg. The genetic basis of steroid-resistant nephrotic syndrome. Paediatr Croat. 2015; 59 (Supl 1): 44-49
Pregled
Review
Paediatr Croat. 2015; 59 (Supl 1): 44-49
THE GENETIC BASIS OF STEROID-RESISTANT NEPHROTIC SYNDROME
YAACOV FRISHBERG*
Nephrotic syndrome (NS) represents disruption of the glomerular filtration barrier which is responsible for plasma ultrafiltration during urine formation. Steroid-resistant nephrotic syndrome (SRNS) progressing to advanced kidney failure, although representing approximately 15% of all cases of childhood NS, is the common phenotype of most of the hereditary forms of NS whether recessive or dominant. Most gene-products associated with SRNS are expressed predominantly in the podocytes or the slit diaphragm.
Currently, the genetic basis of SRNS can be found in less than a third of all families tested. It should therefore be emphasized that
a negative result by candidate gene approach does not rule out a hereditary disease. Identifying disease causing mutations would
have impact not only on the therapeutic regimen adopted and the ability to predict outcome but also would provide a tool for genetic
counseling. This review discusses the scientific background of hereditary NS and explores the indications for routine genetic testing
taking into consideration cost-effectiveness as well. It cannot be over-stated that the availability of genetic tools for diagnosis of renal diseases, should not by any means replace the meticulous clinical evaluation of patients with SRNS by their treating physicians.
It would have a favorable impact on the likelihood of a genetic test to yield the correct diagnosis.
Descriptors: STEROID-RESISTANT NEPHROTIC SYNDROME, CHILDREN, GENES, RECESSIVE, DOMINANT, NEPHRIN, PODOCIN, CANDIDATE
GENE, NEXT GENERATION SEQUENCING
Introduction
Nephrotic syndrome (NS) is characterized by massive proteinuria (over 40
mg/m 2/day) leading to hypoalbuminemia
and edema. The prevalence in the general
population is estimated to be 16/100,000
children (1). Whereas most children with
NS would achieve remission within 4
weeks of daily steroid therapy, 10-20%
remain steroid-resistant (SRNS). At least
50% of patients with SRNS, presenting
in childhood or adolescence, will progress to end-stage kidney disease (ESKD)
within less than a decade of diagnosis,
requiring renal replacement therapy
(RRT) in the form of dialysis or kidney
transplantation. A relatively small group
of patients with SRNS may respond to a
*Division of Pediatric Nephrology,
Shaare Zedek Medical Center and the Hebrew
University School of Medicine, Jerusalem, Israel
Address:
Yaacov Frishberg, MD
Director, Division of Pediatric Nephrology
Shaare Zedek Medical Center
P.O. Box 3235, Jerusalem 91031, ISRAEL
E-mail: [email protected]
44
more intensified immunosuppressive regimen and attain a long-term remission.
Historically, diagnostic evaluation and
prognostic classification of patients with
SRNS were based on the histolopathologic changes detected on kidney biopsies.
The most frequent histologic feature
of SRNS is focal segmental glomerulosclerosis (FSGS), followed by minimal
change disease (MCD) and diffuse mesangial proliferation (DMP).
NS represents disruption of the glomerular filtration barrier, which is responsible for plasma ultrafiltration during
urine formation and is composed of three
layers: the innermost fenestrated endothelial cells followed by the glomerular
basement membrane (GBM) and the
visceral epithelial cells, better known as
podocytes. Since most identified causes
point to the podocytes or the slit diaphragms as pathogenetically involved, the
various forms of NS are referred to as
podocytopathies.
Genetic forms of nephrotic
syndrome
A seminal work by Tryggvason's
group detected mutations in NPHS1 encoding nephrin, a central component of
the slit diaphragm, to be responsible for
the autosomal recessive congenital nephrotic syndrome (CNS) of the Finnish
type (CNF) (2). The slit diaphragm joins
the podocyte foot processes and assists
in maintaining their proper structure and
function. Two founder mutations, designated Fin-major and Fin-minor, are responsible for the vast majority of patients
with CNF in Finland. Evidently, this was
the first example of podcytopathy. It was
followed by the identification of mutations in NPHS2, encoding podocin, causing SRNS in children (3). The common
phenotype was of SRNS presenting in
early childhood with gradual decline in
kidney function until ESKD is reached
usually during the first or second decade
of life. None of the affected patients in the
original report experienced recurrence
of FSGS following kidney transplantation. Podocin is a stomatin protein family
member with a predicted hairpin-like
structure localizing to the insertion site
of the slit diaphragm of podocytes. In a
study by Benzing's group it was demonstrated that wild-type podocin is targeted to the plasma membrane, and forms
homo-oligomers involving the carboxyand amino terminal cytoplasmic domains (4). The association of podocin with
specialized lipid raft microdomains of
the plasma membrane was a prerequisite for recruitment of nephrin into rafts.
In contrast, disease-causing mutations
of podocin failed to recruit nephrin into
rafts either because these mutants were
retained in the endoplasmic reticulum
(R138Q), or because they failed to associate with rafts (R138X) despite their
presence in the plasma membrane. As
lipid raft targeting facilitates nephrin
signaling, failure of mutant podocin to
recruit nephrin into lipid rafts may be
essential for the pathogenesis of NPHS2
mutations.
Over the ensuing 15 years, mutations in a growing number of genes have
been identified in patients with SRNS.
The common denominator of these genes is that they are involved in the development, structure or function of components of the glomerular barrier, most
often the podocytes. The rare exception
is LAMB2 whose gene product is markedly expressed within the GBM (5). To
date, mutations in at least 27 genes, inherited in a recessive or dominant fashion
have been inflicted in SRNS in children
and adults (6).
Recessive mutations are usually
fully penetrant and therefore represent
the etiology of SRNS rather than merely
conveying a risk factor for the disease.
Identification of a causative recessive
mutation would enable the treating team
to achieve the following goals: 1.) providing genetic counseling to families at
risk, including prenatal and pre-gestational diagnosis. 2.) Establishing genotypephenotype correlation. 3.) Transferring
mutations into animal models in order to
study precisely the detrimental effect of
a given genetic variant. 4.) Stratification
of affected individuals according to the
specific mutation in a given gene for the
development of distinct therapeutic studies.
Table 1
Etiology of autosomal recessive nephrotic syndrome
Genes
Locus
Phenotype / comments
NPHS1/nephrin
19q13.1
CNF; occasionally FSGS
NPHS2/podocin
1q25-q31
SRNS: MCD, DMP, FSGS
NPHS3qPLCE1
10q23-q24
DMS, occasionally FSGS
SMARCAL1
2q34-q36
Schimke immune-osseous dysplasia
LAMB2
3p21
Pierson syndrome (DMS)
SCARB2
4q21
NS with C1q deposits; progressive myoclonic epilepsy
COQ6
14q24
Syndromic NS (sensorineural deafness, seizures, ataxia)
PTPRO/GLEPP1
12p12
FSGS/MCD
MYO1E
15q21
FSGS
ITGA3
17q21
Syndromic NS: CNS, interstitial lung disease, skin fragility
COQ2
4q21.23
SRNS, ESKD, epileptic encephalopathy
CUBN
10p.13
Intermittent proteinuria (tubular proteinuria not excluded)
ADCK4
19q13.2
SRNS, occasionally infantile
ITGB4
17q25.1
Cong. FSGS, epidermolysis bulosa
PDSS2
6q21
Risk allele for FSGS; independently, CoQ10 def
ARHGDIA
17q25.3
DMS
CD2AP
6p12.3
FSGS; also dominant inheritance
NEIL1
15q24.2
SRNS
MEFV
16p13.3
Familial Mediterranean Fever
A list of 20 recessive and 6 dominant
genes identified in cases of NS with the
corresponding phenotype are depicted in
Tables 1 and 2, respectively.
It has previously been shown that
85% of patients with CNS, manifesting
before the age of 3 months, and 66% of
individuals with infantile NS, presenting before one year of age, are expla-
ined by causative mutations in one of
the following genes: NPHS1, NPHS2,
LAMB2 and WT1 (7). Scarce data derived from large cohorts were available
for SRNS presenting later in life. Most
recently, a large cohort of patients with
SRNS were studied to detect the frequency of causative mutations. A strategy
of high-throughput, bar-coded exon
sequencing using the Fluidigm platform
Table 2
Etiology of autosomal dominant nephrotic syndrome
Genes
Locus
Phenotype / comments
CD2AP
6p.12.3
FSGS; occasionally recessive inheritance
WT1
11p13
Denys-Drash syndrome; Frasier syndrome; DMS; FSGS
α-actinin-4
19q13
FSGS
TRPC6
11q21-q22
FSGS
LMX1B
9q34.1
Nail patella syndrome
INF2
14q32
FSGS; also Charcot- Marie-Tooth disease
ARHGAP24
4q20
FSGS
45
Y. Frishberg. The genetic basis of steroid-resistant nephrotic syndrome. Paediatr Croat. 2015; 59 (Supl 1): 44-49
with consecutive next-generation sequencing was implemented (6). A proof of
principle of this approach was confirmed
in a small cohort of 96 patients, previously diagnosed by Sanger sequencing of
the relevant gene (8). This technique was
then implemented in a large international cohort of 2,016 cases from 1,783 families. Disease-causing mutations were
found in 526 of 1783 families, representing 29.5%. It should therefore be emphasized that a negative result by candidate
gene approach does not rule out a hereditary disease. A total of 27 genes were
examined but a single-gene cause of
SRNS was found in only 21 of 27 genes.
No causative mutation was identified in
any of the remaining 6 genes. Of note,
9.93% of the families with proven genetic NS had mutations in NPHS2, 7.34%
- in NPHS1, 4.77% - in WT1 and 2.17%
- in PLCE1 implying that in 82% of the
families who tested positive, pathogenic
mutations were detected in 4 out of 27
genes examined. No gender difference
in the likelihood of identifying a diseasecausing mutation was noted. There was
a negative correlation between the likelihood of identifying a disease-causing
mutation and the age of onset of proteinuria: 61.3% of children with infantile
NS compared to approximately 10% of
children over 12 years were found to
have a single-gene mutation in one of the
21 genes. As expected, the detection rate
of disease-causing mutations was much
higher in highly consanguineous families.
Mutations in recessive genes are
more likely to cause SRNS in childhood
whereas dominant mutations are more
prevalent among young adults. The major genetic causes of dominant forms of
NS include mutations in inverted formin
2 (INF2), transient receptor potential cation channel protein, type C6 (TRPC6)
and actinin-alpha 4 (ACTN4). It has been
shown that mutations in INF2 account
for approximately 16% of all cases of
AD SRNS/FSGS mostly in the adult population (9, 10). Unlike AR forms, dominant variants are less penetrant and as a
result affected individuals may even be
asymptomatic. The ultimate phenotype
possibly results from further gene-gene
or gene-environment interactions.
46
Renal histology
It has been appreciated that the
absence of therapeutic response to steroids is a better prognostic factor in children with nephrotic syndrome than the
underlying histology. In fact, patients
with bi-allelic mutations in NPHS2 may
have a full range of histopathologic findings including minimal change, diffuse
mesangial proliferation and FSGS (3, 11).
Furthermore, we have occasionally
encountered IgM and/or C3 mesangial
deposits with otherwise DMP, in these
children which may represent non-specific secondary inflammatory events (11).
Identifying a single-gene cause of SRNS
renders renal biopsy unnecessary as this
will have no bearing on the treatment
of choice or the long-term prognosis.
Furthermore, the histopathological findings cannot distinguish genetic from
non-genetic disease etiologies (12).
Extra-renal manifestations
The vast majority of patients with
monogenic causes of SRNS have isolated kidney disease. In 17.3% of patients
enrolled in the PodoNet consortium, at
least one extra-renal abnormality was
reported (12). The most common organ
system involved was the central nervous
system manifesting with brain structural
anomaly, microcephaly and/or psychomotor delay.
Other systemic features stem from
the pathogenetic mechanisms derived
from the specific gene involved. For instance, sexual differentiation defects and
Wilms' tumor are prevalent among individuals with the Denys-Drash or Frasier
syndromes harboring mutations in WT1.
The association of cardiac defects, particularly left ventricular hypertrophy (in
the absence of hypertension or kidney
failure), pulmonary stenosis (valvar, supravalvar or peripheral) and discrete sub
aortic stenosis has been noted in children
homozygous for the R138X mutation in
NPHS2 (13). This may reflect the expression of NPHS2 mRNA in fetal, but not
in adult, heart.
Y. Frishberg. The genetic basis of steroid-resistant nephrotic syndrome. Paediatr Croat. 2015; 59 (Supl 1): 44-49
Genotype-phenotype
correlation
The age of onset of NS was significantly earlier for children with splice
site mutations in PLCE1 compared to
missense mutations or C-terminal truncating mutations (6). Similar correlation
could not be drawn between mutation
types involving other genes relevant to
recessive forms of SRNS. Koziell described a cohort of patients from Malta with
a founder truncating mutation in NPHS1
(R1160X) (14). Interestingly, there was a
discordant CNF phenotype which may
have been influenced by gender. Whereas most boys had the typical phenotype and many succumbed to the disease,
girls tended to have a mild phenotype
with the extreme being a 19-year-old girl
with mild proteinuria, normal serum albumin and normal kidney function.
Steroid-Sensitive Nephrotic
Syndrome (SSNS)
Not surprisingly, none of the 185
children with SSNS, who composed a
control group in the large international
cohort of children with SRNS, was found to carry bi-allelic mutations in any
of the 27 genes which were associated
with SRNS (6). This supports the notion
that patients with single-gene cause of
SRNS are unlikely to respond to steroids
but may rather suffer from side-effects
of this therapeutic modality (11, 15).
Most recently, it was shown that heterogeneous genetic variants in sporadic
nephrotic syndrome associate with not
only resistance to steroids but to other
immunosuppressive agents (16). A recent report from Hildebrandt’s group
described bi-allelic mutations in EMP2,
encoding epithelial membrane protein 2,
in 4 individuals from 3 unrelated families with NS (17). Interestingly, in two
families from Turkey the disease responded to steroids and in the fourth child of
African-American ancestry it was steroid-resistant. The precise pathogenetic
mechanism underlying this entity with
special emphasis on its varying response
to steroids remains unclear.
There are anecdotal reports of patients with genetic forms of NS who responded to immunosuppressive regimen.
Two patients with bi-allelic mutations
in PLCE1 seemed to attain remission
following treatment with cyclosporine
A (CsA) (18). Whether this represents
the non-immunological anti-proteinuric
effect of CsA remain to be proven. It
has been shown that CsA can stabilize
the actin cytoskeleton by blocking the
calcineurin-mediated dephosphorylation
of synaptopodin (19). Alternatively, this
may be an example of the phenotypic variability which can be mutation-specific
or even within the context of the same
genotype.
yet unknown interaction with a modifier
gene or an environmental factor. This
should be taken more seriously in dominant forms which may involve poorly penetrant alleles resulting in asymptomatic
affected individuals. Living-related potential donors would have to be screened
for the relevant mutation prior to declaring them suitable for kidney donation.
Obviously, living-related donations from
family members of individuals with hereditary kidney disease but unknown genetic defects should be discouraged.
Non-immunologic modalities that
have been shown to slow the progression
of proteinuric renal diseases, including
angiotensin converting enzyme inhibitors (ACEi) or lipid lowering agents
should be considered in every child with
SRNS regardless of whether they have
genetic forms of NS.
Is routine genetic testing for NS
justified?
Post-transplant recurrence
of FSGS
Recurrence of FSGS was found in
15% of patients undergoing kidney transplantation in the PodoNet consortium
(12). It occurs almost exclusively among
individuals without a genetic diagnosis
which implies that a circulating permeability factor is involved, likely amenable
to treatment with immunosuppressants
and plasmapheresis. Proteinuria post
kidney transplant has been detected in a
child with bi-allelic mutations in NPHS2
encoding podocin, although antibodies
to podocin could not be identified (20).
This is in contrast to children with CNF
due to mutations in NPHS1 encoding
nephrin who may develop proteinuria
after kidney transplantation secondary
to acquired circulating anti-nephrin antibodies (21).
It is unlikely that living-related
asymptomatic kidney donors who are
carriers of recessive mutations have
additional risk of developing CKD in the
future. This has been exemplified by a
report of 4 living-related kidney donors,
heterozygous for mutations in NPHS2,
who remain healthy. Also, none of the
corresponding recipients developed proteinuria following kidney transplantation (20). The only reservation would be a
Any genetic test ordered should
address the following three goals (22):
●● Would the result of this test help establishing the diagnosis?
●● Would the result likely to assist in
planning the treatment?
●● Is the result from the proband likely
to produce data on the risk of other
family members?
Given the data presented here, it is
reasonable to conclude that genetic testing is justified in the following subgroups of patients with NS:
●● All children with CNS (onset prior to
3 months of age).
●● All children with infantile NS (onset
3-12 months of age).
●● If NS is part of malformations in
other organ systems.
●● All patients with a family history of
NS and/or chronic kidney disease
(CKD).
Whether it should be recommended
in every child with SRNS, is still questionable. If the treating physician has free
access to the high throughput screening
platform covering 27 genes that have
been associated with SRNS, this should
be implemented. Otherwise, a reasonable approach would be to screen those
patients for the 4 genes that account for
over 80% of children with genetic NS
(NPHS1, NPHS2, WT1 and PLCE1). The
order of screening may be affected by the
age of onset of proteinuria: NPHS1, WT1
and PLCE1 first, in congenital or infantile NS and NPHS2 first in older children.
Although it may change in the near
foreseeable future with rapid technical
advancement in the field, at this point in
time, next-generation sequencing should
still be reserved for well selected cases
performed in research laboratories. The
advantage of this approach is that it can
screen all of the coding regions or the
entire genome in one run and may yield
not only causing mutations in known
genes but may also discover new genes
that have not been associated with NS
before. Identifying new genes may shed
light on the pathophysiological mechanisms underlying various forms of NS and
additionally, may pave the path for the
development of specific therapeutic modalities. The amount of data generated
by this technique requires a well trained
team in the area of bioinformatics in order to wisely analyze all the genetic variants which may bear deleterious effect.
This would carry significant ethical dilemmas which should be taken seriously
into consideration.
The availability of rapid and costeffective genetic tests, should not replace
the meticulous clinical evaluation of patients with SRNS by their treating physicians. Furthermore, this would have a favorable impact on the likelihood of a genetic test to yield the correct diagnosis.
Availability of genetic
testing
One of the challenges faced by
physicians taking care of children with
SRNS is to determine what genetic tests
are currently available. The following
free resource: www.genetests.org provides updated information on the disease,
gene, protein and the laboratory performing the genetic test. Whether this test is
covered by the medical insurance company is another challenge and may be
country-specific or even insurer-specific.
The type of laboratory performing the
test (research- versus approved clinical
laboratory) may impact on the likelihood
that the expenses will be reimbursed.
47
Y. Frishberg. The genetic basis of steroid-resistant nephrotic syndrome. Paediatr Croat. 2015; 59 (Supl 1): 44-49
From private mutations
to private genes
The discovery that mutations in
NPHS1 cause CNF had great impact not
only on our understanding of the pathogenesis of this clinical entity but also
provided the medical community with a
tool to diagnose a significant portion of
their patients with CNF. CNF is inherited in an autosomal recessive fashion
and has a worldwide distribution. It was
realized that distinct mutations than those detected in Finland are responsible for
CNF in other ethnic groups. It was quite
striking to detect three different mutations in NPHS1 in one village near Jerusalem, Israel (23). Most of the inhabitants
of this community are descendants of
one Muslim family and have maintained
their isolation by preference of consanguineous marriages.
As more and more genes have been
identified as associated in their mutated
form with SRNS, it was clear that every
"new" gene provides explanation to a
very small portion of the patient population. Mutations in 4 genes are responsible
for SRNS in 24.2% of the 1,783 families
tested, whereas mutations in 17 different genes cause SRNS in only additional 5.3% of the families (6). The genetic
basis of SRNS in the remaining 70.5%
of the families remains elusive. Also,
mutations in EMP2 leading to NS, were
identified in a single family from Turkey
and subsequent screening of 1,600 individuals from an international cohort of
patients with NS yielded two additional
cases, implying that this is a rare cause
of NS (17). Taken together, there seems
to be a shift from "private" mutations in
common genes to mutations in "private"
genes. This may dictate novel strategies
to identify genetic causes of renal diseases which may include searching for genetic variants in non-coding regions or
epigenetic alterations.
A report of the International Study of Kidney
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LITERATURE
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Spectrum of steroid-resistant and congenital
nephrotic syndrome: The PodoNet registry
cohort. Clin J Am Soc Nephrol. 2015 [Epub
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syndrome: is it all podocin? J Am Soc Nephrol.
2006; 17: 227-31.
Autor izjavljuje da nije bio u sukobu interesa.
Author declare no conflict of interest.
48
Y. Frishberg. The genetic basis of steroid-resistant nephrotic syndrome. Paediatr Croat. 2015; 59 (Supl 1): 44-49
Sažetak
14.Koziell A, Grech V, Hussain S, et al. Genotype/
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EMP2 cause childhood-onset nephrotic syndrome. Am J Hum genet. 2014; 94: 884-90.
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38: 1397-405.
GENETSKA PODLOGA STEROID-REZISTENTNOG NEFROTSKOG SINDROMA
Y. Frishberg
Nefrotski sindrom (NS) predstavlja poremećaj glomerulske filtracijske barijere koja je odgovorna za plazmatsku ultrafiltraciju
za vrijeme stvaranja urina. Iako predstavlja oko 15% svih slučajeva NS u djetinjstvu, steroid-rezistentni nefrotski sindrom (SRNS)
koji progredira u bubrežno zatajenje, je najčešći oblik nasljednog NS, a može biti recesivan ili dominantan. Većina genskih produkata povezanih sa SRNS se predominantno pojavljuju u podocitima ili na filtracijskoj membrani. Trenutno genska podloga SRNS može
biti pronađena u manje od trećine analiziranih obitelji pa treba naglasiti da negativni rezultati potrage za kandidatnim genom ne
isključuje da se radi o nasljednoj bolesti. Identificiranje mutacije koja uzrokuje bolest je važno ne samo za terapijski pristup, ishod
liječenja, nego je i osnova za genetsko savjetovanje. U ovom preglednom radu se raspravlja o znanstvenoj podlozi nasljeđivanja
NS te indikacijama za rutinsko gensko testiranje uzimajući u obzir i financijsku isplativost. Mogućnost genskog testiranja u svrhu
otkrivanja bubrežne bolesti ipak ne može zamijeniti pomnu kliničku evaluaciju bolesnika sa SRNS od strane nadležnog liječnika
nego je važan čimbenik da se s većom vjerojatnošću postavi točna dijagnoza.
Deskriptori: STEROID-REZISTENTNI NEFROTSKI SINDROM, DJECA, GENI, RECESIVNO, DOMINANTNO, NEFRIN, PODOCIN, KANDIDATNI
GENI, NEXT GENERATION SEKVENCIONIRANJE
Primljeno/Received: 6. 4. 2015.
Prihvaćeno/Accepted: 8. 4. 2015.
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Recurrent nephrotic syndrome in homozygous
truncating NPHS2 mutation is not due to antipodocin antibodies. Am J Transplant. 2007; 7:
256-60.
21.Patrakka J, Ruotsalainen V, Reponen P, et al.
recurrence of nephrotic syndrome in kidney
grafts of patients with congenital nephrotic
syndrome of the Finnish type: Role of nephrin.
Transplantation. 2002; 73: 394-403.
22.Gbadegesin R, Winn M, Smoyer WE. Genetic
testing in nephrotic syndrome: Challenges and
opportunities. Nat Rev Nephrol. 2013; 9: 17984.
23.Frishberg Y, Ben-Neriah Z, Suvanto M, et al.
Misleading findings of homozygosity mapping
resulting from three novel mutations in NPHS1
encoding nephrin in a highly inbred community. Genet Med. 2007; 9: 180-4.
49