NDT Advance Access originally published online on December 8, 2007
Nephrology Dialysis Transplantation 2008 23(4):1291-1297; doi:10.1093/ndt/gfm759
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Mutations in PLCE1 are a major cause of isolated diffuse mesangial sclerosis (IDMS)
1 Departments of Pediatrics and of Human Genetics, University of Michigan, Ann Arbor, MI 48109, USA 2 Service de nephrologie, hôpital Robert-Debré, Paris, France 3 Department of Pediatrics, Unit of Nephrology, Hacettepe University, Ankara, Turkey 4 Sindh Institute of Urology and Transplantation, Karachi, Pakistan 5 Department of Pediatric Nephrology, Kinderspital Zürich, Zürich, Switzerland 6 Department of Pediatric Nephrology and Dialysis, Schneider Children's Medical Center of Israel, Petah Tiqva, Israel 7 Department of Nephrology, Mattel Children's Hospital at UCLA, Los Angeles, California, USA 8 Inserm U-574, Hôpital Necker-Enfants-Malades, Paris, France 9 Department of Medicine, Division of Nephrology University of Michigan, Ann Arbor, USA 10 Department of Human Genetics, Friedrich-Alexander-Universität, Erlangen-Nürnberg, Germany 11 Department of Pediatrics, Duke University, Durham, NC 27710 USA
Friedhelm Hildebrandt, University of Michigan Health System, 8220C MSRB III, 1150 West Medical Center Drive, Ann Arbor, MI 48109-0646, USA. Tel: +1 734 615-7285 (office), +1 734 615-7895, -7896 (laboratories); Fax: +1 734-615-1386, -7770; Email: fhilde{at}umich.edu
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Abstract |
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Background and objectives. Diffuse mesangial sclerosis (DMS) is a histologically distinct variant of nephrotic syndrome (NS) that is characterized by early onset and by progression to end-stage kidney disease (ESKD). Besides syndromic DMS, isolated (non-syndromic) DMS (IDMS) has been described. The etiology and pathogenesis of DMS is not understood. We recently identified by positional cloning recessive mutations in the gene PLCE1/NPHS3 as a novel cause of IDMS. We demonstrated a role of PLCE1 in glomerulogenesis. Mutations in two other genes WT1 and LAMB2 may also cause IDMS. We therefore determine in this study the relative frequency of mutations in PLCE1, WT1 or LAMB2 as the cause of IDMS in a worldwide cohort.
Methods. We identified 40 children from 35 families with IDMS from a worldwide cohort of 1368 children with NS. All the subjects were analyzed for mutations in all exons of PLCE1 by multiplex capillary heteroduplex analysis and direct sequencing, by direct sequencing of exons 8 and 9 of WT1, and all the exons of LAMB2.
Results. The median (range) age at onset of NS was 11 (1–72) months. We detected truncating mutations in PLCE1 in 10/35 (28.6%) families and WT1 mutations in 3/35 (8.5%) families. We found no mutations in LAMB2.
Conclusions. PLCE1 mutation is the most common cause of IDMS in this cohort. We previously reported that one child with truncating mutation in PLCE1 responded to cyclosporine therapy. If this observation is confirmed in a larger study, mutations in PLCE1 may serve as a biomarker for selecting patients with IDMS who may benefit from treatment.
Keywords: IDMS; LAMB2, mutation; PLCE1, WT1
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Introduction |
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Diffuse mesangial sclerosis (DMS) is a clinico-pathological entity that was first described in 1985 [1]. The disease is characterized by onset of nephrotic syndrome (NS) in the first year of life and rapid progression to end-stage kidney disease (ESKD). Pathologically, findings include mesangial matrix expansion with no mesangial hypercellularity, hypertrophy of the podocytes in early disease, thickened basement membranes, diminished patency of capillary lumen and hypertrophied and vacuolized podocytes, which surround the glomerular tufts like a crown in advanced disease [2]. DMS has been described as part of syndromes such as Denys-Drash syndrome (DDS). DDS includes ambiguous genitalia, Wilm's tumor and DMS caused by mutation in the WT1 gene [3]. Pierson syndrome is defined by the association of mental retardation, microcoria and DMS caused by mutation in LAMB2 gene [4]. However, non-syndromic isolated DMS (IDMS) can also occur, and there have been suggestions in the past that it may be inherited in an autosomal recessive fashion, although few cases due to dominant WT1 mutations have been reported in the literature [1,2]. We have recently identified PLCE1 mutations as a novel cause of DMS [5].
The PLCE1 gene resides on chromosome 10q23. The gene encodes phospholipase C epsilon 1 (PLC
1). PLC1 is a member of the phospholipase family of enzymes that catalyzes the hydrolysis of polyphosphoinositides to generate second messengers, such as inositol-1,4,5 trisphosphate and diacylglycerol [6]. These second messengers are involved in cell growth and differentiation [6]. PLC1 is expressed in the podocyte of the glomerulus, neural tissue and skeletal muscle of mouse embryos, as well as the skin, skeletal muscle and heart of adult mice [7–9].
The WT1 gene is on chromosome 11p13 and it encodes a zinc-finger nuclear transcription factor that regulates the expression of other genes by binding DNA [10]. It is expressed in podocytes and in the gonads. The locus for LAMB2 is on chromosome 3p21 [4]. The gene encodes laminin β2, a component of laminin, an extracellular glycoprotein that is an essential component of the basement membrane [4,11–12]. Laminin β2 is widely expressed in the glomerular basement membrane where it plays a key role in anchoring and differentiation of podocyte foot processes [4]. It is also expressed in ocular tissue and skeletal muscle [4,13]. The mechanisms by which these three distinctly different genes cause DMS are unknown. There are, however, data to suggest that each of them may be important during critical stages of glomerulogenesis and mutation of the genes may cause disruption of the process [4,5,14,15].
NS due to DMS characteristically presents in the majority of cases within the first year of life and there is no clear-cut guideline for therapy. However, some reported cases with presentation in the first year of life have been found to be steroid resistant [16]. Interestingly, a child with PLCE1 loss of function mutation and DMS histology responded to cyclosporine therapy [5]. The mechanism by which this occurs is unknown; however, this observation for the first time offers a possible biomarker for therapy responsive DMS.
To further define the relative frequencies of PLCE1 and other genes (WT1 and LAMB2) known to cause DMS, we performed mutational analysis of PLCE1, WT1 and LAMB2 in a worldwide cohort of children with IDMS.
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Materials and methods |
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We identified 57 children with IDMS from a worldwide cohort of children with NS. We have previously reported mutations in eight of these children (six families) before [5,17].
Clinical data
Inclusion criteria were: (i) early-onset proteinuria, generalized edema and hypoalbuminemia; (ii) classical histologic findings of DMS as described in the introduction; (iii) absence of disease-causing mutations in NPHS2 (podocin) and (iv) absence of disease-causing mutations in NPHS1 (nephrin) in children aged 0–3 months. Exclusion criteria were: (i) presence of constellation of extra renal signs that may suggest Pierson's syndrome (DMS, mental retardation or ocular changes) or DDS (DMS, ambiguous external genitalia and Wilm's tumor) and (ii) other extra renal disease symptoms and signs.
Approval for the study was granted by the Institutional Review Board (IRB) of the University of Michigan Medical School, Ann Arbor. Informed consent was obtained from all of the study subjects and/or their parents. Clinical information was obtained from the study subjects. This included basic demographic data such as age, gender, race or ethnicity, history of parental consanguinity and family history of renal disease, specifically NS, age at onset of symptoms, age at onset of proteinuria, associated hematuria, generalized edema and elevated blood pressure. Also recorded were the presence of extra renal symptoms and signs such as ambiguous genitalia, history of Wilm's tumor, mental retardation, microcoria and visual disturbances. When applicable, age at onset of ESKD, commencement of renal replacement therapy, history of kidney transplantation and recurrence of primary disease in renal allograft were recorded. Serum creatinine, urine protein/creatinine ratio and glomerular filtration rate at the time of data acquisition were obtained.
Mutation analysis
Genomic DNA was extracted from whole blood samples using standard methods [18].
PLCE1: We used a two-step approach for mutation analysis in PLCE1. First, patients were screened by exon-PCR using multiplex capillary heteroduplex analysis (MCHA) that has a >95% detection rate [19]. Samples were run on a MegaBACE 1000 DNA analysis system (GE Healthcare). The results were analyzed using the Genetic profiler v.2.0 software (GE Healthcare). Secondly, samples with aberrant peak patterns on MCHA were directly sequenced by the dideoxy chain termination method using the capillary ABI sequencer at the University of Michigan sequencing core facility. Sequences were evaluated for mutations using the SequencherTM software (Gene Codes Corporation, Ann Arbor, MI, USA). All mutations were confirmed by sequencing of the complementary strand. Where parental samples were available, segregation analysis was carried out to confirm the mutation.
WT1: The mutation bearing exons 8 and 9 of the WT1 gene were screened using exon flanking primers as previously described [17] and mutations were confirmed by sequencing of the complementary strands.
LAMB2: Exon flanking primers for all the 32 exons of LAMB2 were developed in the laboratory of MZ. Bidirectional direct sequencing was carried out using the Big Dye Terminator Cycle Sequencing Kit (Applied Biosystems) on the ABI 3730 capillary sequencer (Applied Biosystem) in the same laboratory.
All the primer sequences and PCR conditions for PLCE1, WT1 and LAMB2 mutation analysis are available on request.
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Results |
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A total of 57 children with DMS were identified from a cohort of 1368 children with NS. Fourteen of these children were found to have structural anomalies in at least two organ systems and were therefore excluded from further analysis. One child with a WT1 mutation was reported to have developed Wilm's tumor during subsequent follow-up and two children were found to have disease-causing mutations in nephrin (NPHS1) and were therefore excluded from the study. The remaining 40 children from 35 families are the subjects of this report.
Mutational analysis
Mutations were detected in PLCE1 and WT1 in 13/35 (37%) of the families studied.
PLCE1/NPHS3: A total of 10 different mutations were found in 10/35 (28.6%) families (14 children) (Table 1). Eight of the ten families are known to be consanguineous. In this cohort of 35 families, mutations in PLCE1 cause IDMS in 10/35 (28.6%) of the families. Except in one family, all the mutations detected were homozygous loss of function (frameshift or stop codon) mutations. One child (A1407) has two compound heterozygous loss of function mutations (splice site) in exons 9 and 14. Four of these mutations have been previously reported [5]. Table 1 shows the clinical characteristics of the children with mutations. The six novel mutations are shown in Figure 1. We did not find any of the mutations in at least 75 healthy Turkish and Central European control individuals.
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WT1: We found single heterozygous mutations in 3/35 (8.5%) of all the families with IDMS (Table 1). All the children from the three families are females with a 46XX karyotype. One of the three children died shortly after diagnosis. The other two children have been followed up for 2–4 years with serial ultrasound and they have not developed Wilms tumor or any other extra renal symptoms since diagnosis. Two of the three mutations have previously been reported in our study on the role of WT1 in the etiology of steroid-resistant NS and NS in the first year of life (Table 1) [17,20]. The third mutation (Q369H) is a novel mutation that was not found in 100 healthy individuals.
LAMB2: We found no mutation in any of the exons of LAMB2.
Genotype phenotype correlations
Statistical evaluations of clinical characteristics of the study population are shown in Table 2. Information on consanguinity was available in 34/35 families; 11 families were known to be consanguineous.
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Mutations were detected in PLCE1 and WT1 in 13/35 (37%) of the families studied.
There was no difference in age at onset of disease, gender distribution or response to therapy between the group of children with mutations and the group with no mutations in any of the three genes (Table 2). However, children from 8/13 families with mutations are from a consanguineous union compared with 3/21 for the group with no mutation (P = 0.002, Table 2).
The median age of onset of disease in children with PLCE1 mutations was 9 months (range 1–48 months). The three patients with WT1 mutations presented in the first year of life. The median age at onset of disease in all the children with no mutation in any of the three genes was 10 months (range 1–72 months); there was no difference in age of onset between the children with mutations and those with no mutations. Since in routine clinical practice, children with early-onset NS and/or DMS are not routinely offered immunosuppressive treatment, only 14 out of the 40 children in this cohort were treated. In this group, eight children had mutations (seven in PLCE1 and one in WT1) and six children had no mutation. All the children were therapy resistant except one child (A38 II-4) with PLCE1 loss of function mutation who responded to cyclosporine and angiotensin converting enzyme inhibitor (ACEI) therapy; this child was reported before [5]. This child has been followed for 12 years and he is now in complete remission with normal kidney function. At the time of the last follow-up, 25 of the 40 children are known to be in ESKD. They comprised 10 children with mutations and 15 with no mutations in any of the three genes. The children with no mutation tended to reach ESKD later than children with mutations (median age 24 versus 10 months Kruskal Wallis P = 0.016, Table 2). Sixteen of the forty children underwent kidney transplantation. Seven of these had mutations and nine had no mutation. None of the children are known to have recurrence of DMS in their renal allograft at the time of the last follow-up.
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Discussion |
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In this study, we detected recessive PLCE1 mutations as the most frequent (28.6%) and WT1 mutations as the second most frequent (8.5%) cause of IDMS in a worldwide cohort of 36 families.
The etiology of non-syndromic DMS is largely unknown. However, it has been suspected for more than 20 years that it may be at least in part, an autosomal recessive genetic disease [1]. Recent identification of mutations in PLCE1 as a cause of early-onset NS that may manifest with a DMS histopathologic feature by our group prompted us to perform mutation analysis in all genes that have been previously reported to cause DMS. As far as we know, the cohort of patients in this study represents one of the largest series of patients with IDMS ever reported in the literature. We found that 37.1% of the families in this series have IDMS that can be explained by homozygous mutations in PLCE1 (28.6%) or dominant heterozygous mutations in WT1 (8.5%). Of these two genes, mutations in PLCE1 account for the majority of cases being responsible for 28.6% of all mutations. We found no mutations in LAMB2 in this cohort. In families of subjects with PLCE1 mutations, in whom parental DNA was available, segregation analysis was found to be consistent with an autosomal recessive mode of inheritance thus confirming our identification of PLCE1 as a new cause of IDMS [5].
In this series, 8 of the mutations detected in PLCE1 are loss of function (frameshift or stop codon) mutations. One patient had compound heterozygous loss of function (splice site mutations). We found no missense mutations in this series. Furthermore, apart from two families with the same mutation in exon 14, each family has its own private mutation with no clustering around any exons or specific region of the PLCE1 gene. Thus there is no founder effect in this series. Mutations in PLCE1 are not confined to any part of the world, as we were able to detect mutations in families from Europe, North America, Asia and the Middle East, with the majority of the cases ascertained from Turkey (Table 1).
One of the mutations in WT1 Q369H is a novel mutation that was not found in 100 healthy individuals. This mutation is in exon 8, which encodes for the zinc finger domain of the WT1 protein. The glutamine residue in position 369 is conserved in evolution down to the fish tetraodon. The other two mutations have been previously reported in children with DDS or IDMS [10]. We found only three patients with WT1 mutation in this study; this is consistent with a recent review of the literature by Niaudet et al. where only about 17% of patients with IDMS were found to have mutations in WT1 [21]. Apart from an isolated case from a Japanese study, virtually all cases of IDMS due to mutations in WT1 are found exclusively in exons 8 and 9, which encodes for zinc fingers 2 and 3, respectively [17,20–24]. It is therefore unlikely that we have missed cases of IDMS due to mutations in other exons of WT1.
The mechanisms by which mutations in PLCE1 cause DMS are still under investigation. However, there are data to suggest that PLC1 may serve as an assembly scaffold for organization of a molecular complex involved in glomerular development at the capillary loop stage of glomerulogenesis [5]. Evidence for this is the finding that PLC1 interacts with GTPase-activating protein 1 (IQGAP1) which is found at the basal aspect of the developing podocyte where foot processes are forming and which is also known to interact with nephrin [5,25]. It has been observed that patients with WT1 mutations have loss of downregulation of PAX2 gene by WT1, which leads to persistent expression of PAX2 in podocytes [14,15]. This mechanism is further supported by findings of a severe congenital NS phenotype in PAX2 transgenic mice [26]. The majority of the children in this study presented with NS within the first year of life although some presented later on in life (Tables 1 and 2]. Mutations in PLCE1 therefore expanded the genetic causes of NS in the first year of life [20]. The age at onset of symptoms was not different between patients with WT1 mutations and patients with PLCE1 mutations (Table 2). Neither is there a difference between patients with and without mutations (Table 2). Age of onset therefore does not appear to be a discriminant factor for the presence of mutations. However, children without mutations in PLCE1, WT1 and LAMB2 seem to have slower progression of disease and reached ESKD at an older age (Table 2). Although we did not detect any patients with missense mutations in PLCE1, it is plausible to speculate that missense mutations in PLCE1 may be associated with milder disease course or other histologic variants such as focal segmental glomerulosclerosis (FSGS) [5]. Since 36% of consanguineous offsprings with IDMS did not have mutation in PLCE1, WT1 or LAMB2, it is likely that known genes and other unidentified mutated genes account for the remaining cases. Only 14 children were placed on corticosteroid or cyclosporine therapy in this series. We did not find any child with therapy response apart from the child with a PLCE1 mutation that we previously reported [5]. This may be due to the fact that children with DMS and early-onset NS are not routinely offered treatment. There is a need for further study to screen children with IDMS due to mutations in PLCE1 for therapy response. The mechanism of response to steroid and other immunosuppressive agents in children with mutations is not clear. There is a need for further study to explain this. However, if more children with mutations in PLCE1 are found to be therapy responsive, there may be a case for controlled treatment with corticosteroids and other modalities of treatment in a subset of children with IDMS.
In conclusion, PLCE1 is a major cause of IDMS in this worldwide series. As there is a possibility that the disease may be potentially amenable to treatment, further study is needed. We would suggest screening for mutations in PLCE1 in children with IDMS.
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National Institutes of Health (R01-DK076683 and P50-DK039255 to FH; R01-DK46073 to RW). Grants to FH from the KMD Foundation and from the Thrasher Research Foundation. FH is the Frederick G.L. Huetwell Professor and a Doris Duke Distinguished Clinical Scientist. Grants to MZ from the German Research Foundation (DFG).
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Acknowledgments |
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We would like to thank the patients and their parents for their participation in this study. We acknowledge our collaborators worldwide for contribution of patient information, especially Drs L. Basel (Tel Aviv, Israel), M. Griebel (Munich, Germany), M.Pohl (Freiburg, Germany), D. Mueller (Berlin, Germany), R. Bogdanovic (Belgrade, Serbia) and C. Mache (Graz, Austria). We thank R. Lyons for excellent DNA sequencing.
Conflict of interest statement. None declared.
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Accepted in revised form: 24. 9.07
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