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NDT Advance Access originally published online on September 12, 2006
Nephrology Dialysis Transplantation 2006 21(11):3133-3138; doi:10.1093/ndt/gfl347
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© The Author [2006]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Genetics and clinical features of 15 Asian families with steroid-resistant nephrotic syndrome

Akiko Kitamura1,*, Hiroyasu Tsukaguchi2,*, Kazumoto Iijima3,*, Jungo Araki4, Motoshi Hattori5, Masahiro Ikeda6, Masataka Honda6, Kandai Nozu7, Hitoshi Nakazato8, Norishige Yoshikawa9, Shoji Kagami1, Masaaki Muramatsu4, Yong Choi10, Hae Il Cheong10 and Toshio Doi2

1Department of Pediatrics and 2Department of Clinical Biology and Medicine, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, 3Department of Nephrology, National Center for Child Health and Development, Tokyo, 4Department of Molecular Epidemiology, Tokyo Medical and Dental University, Tokyo, 5Department of Pediatric Nephrology, Tokyo Women's Medical University, Tokyo, 6Department of Pediatric Nephrology, Tokyo Metropolitan Kiyose Children's Hospital, Tokyo, 7Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, 8Department of Pediatrics, Kumamoto University School of Medicine, Kumamoto and 9Department of Pediatrics, Wakayama Medical University, Wakayama, Japan and 10Department of Pediatrics, Seoul National University Children's Hospital, Seoul, Korea

Correspondence and offprint requests to: Hiroyasu Tsukaguchi, Department of Clinical Biology and Medicine, Institute of Health Biosciences, The University of Tokushima Graduate School, 3-18-15 Kuramoto, Tokushima 770-8503, Japan. Email: hiroyasu{at}clin.med.tokushima-u.ac.jp Kazumoto Iijima, Department of Nephrology, National Children's Medical Center, National Center for Child Health and Development, 10.1, Okura 2chome, Setagaya-ku, Tokyo 157-8535, Japan. Email: iijima-k{at}ncchd.go.jp

Keywords: FSGS; linkage; mutation; nephrotic syndrome; podocyte



   Introduction
Top
 Introduction
Subjects and methods
 Results
 Discussion
 Acknowledgements
 References
 
Steroid-resistant nephrotic syndrome (SRNS) represents a clinically heterogeneous group that is resistant to immunosuppressive therapy and tends to progress to end-stage renal disease (ESRD) within 10 years. The most prevalent renal histology is a focal segmental glomerulosclerosis (FSGS), which is the principal cause of ESRD and accounts for 20 and 5% of all the cases of renal failure, in children and adults, respectively. The clinical hallmarks are sharply contrasted with those of the most common ‘steroid-sensitive’ nephrotic syndrome, which displays responses to steroid therapy. The patients with this steroid-sensitive type have usually minimal histological changes (minimal change nephrotic syndrome, MCNS) and have a favourable long-term outcome. In comparison with MCNS, FSGS is a disease with substantial morbidity, and elucidation of the pathogenesis has been, therefore, a focus of research efforts.

Over the past decade, researchers have attempted to identify the genetic components in a monogenic variant of familial SRNS. Nephrotic syndrome generally occurs sporadically, but familial cases of both autosomal dominant, and recessive, inheritance have been reported. Genes of autosomal dominant families have been mapped to chromosomes 19q13, 11q21–22 and 11q24 [1–3]. Mutations in {alpha}-actinin-4 and in TRPC6 have been identified in a large family mapping to 19q13 and 11q21–22 [4,5], respectively. Four loci have been found to be linked with the autosomal recessive form of nephrotic syndrome: 19q13 [6], 1q25–31 [7], 14q24.2 [8] and 2p12-p13.2 [9]. The disease-causing genes NPHS1 and NPHS2, which encode nephrin and podocin, respectively, have been identified in the families mapping to 19q13 and 1q25–31, respectively [10,11]. NPHS1, which encodes nephrin, has been identified as a causative gene of autosomal recessive Finnish-type congenital nephrotic syndrome (CNF) [10]. Nephrin belongs to the immunoglobulin superfamily expressed at the slit diaphragm between podocyte foot processes. The eight immunoglobulin(Ig)-like domains of nephrin are thought to have anti-parallel trans-interaction and bridges over the adjacent foot processes [12]. NPHS2 has been shown to be mutated in autosomal recessive SRNS [11], which is characterized by early childhood onset of proteinuria, rapid progression to ESRD and renal histology of FSGS. NPHS2 encodes podocin, an integral membrane protein that has a hairpin loop structure and belongs to the stomatin protein family. Podocin is exclusively expressed in podocyte foot processes near the slit diaphragm, but its function is unclear [11]. NEPH1, is an Ig-like molecule expressed at the slit diaphragm, and interacts with nephrin and podocin [13]. NEPH1 null mice developed renal pathological changes of FSGS [14], but human NEPH1 mutations have yet to be clearly demonstrated.

The genetic and clinical features of familial SRNS have not been fully studied in Asian patients. More than 60 unique NPHS1 mutations have been reported in Caucasian countries [15] and NPHS2 is mutated in 26–38% of the familial and 10.5–23% of the sporadic SRNS in a large European survey [16–18]. Even though NPHS1 and NPHS2 mutations have recently been recognized in some Japanese patients with early-onset nephrotic syndrome [19,20], we found no NPHS2 mutations in 36 Japanese sporadic SRNS cases [21], suggesting a significant ethnic difference in disease genes. These observations point to a need for worldwide study to investigate the nature of disease genes in SRNS families outside Caucasian countries. In the present study, we screened the linkage of the NPHS1, NPHS2 and NEPH1 in 15 SRNS families (10 Japanese and five Korean) and subsequently performed mutational analysis. The results excluded involvement of the three loci in all 15 families, suggesting that NPHS1 and NPHS2 variants are relatively restricted to Europeans and that as yet unknown genes are involved in Asian SRNS.



   Subjects and methods
Top
 Introduction
 Subjects and methods
Results
 Discussion
 Acknowledgements
 References
 
Phenotype characterization
We recruited 15 SRNS families on the basis of the following clinical criteria: (i) age of onset between 3 months and 10 years; (ii) rapid progression to ESRD before the age of 15 years; (iii) steroid resistance, defined as persistence of heavy proteinuria (≥50 mg/kg/day) and plasma albumin level <2.5 g/dl after 4 weeks on orally administrated prednisolone 60 mg/m2/day [22]. Subjects were considered ‘affected’ if they had proteinuria >2 g per day, biopsy-proven FSGS, ESRD or had undergone kidney transplantation. Partial response was defined as disappearance of oedema, an increase in the serum albumin concentration to >35 g/l, and the persistence of proteinuria of >4 mg/m2 per h [22]. Among affected individuals, those with secondary FSGS due to other systemic disorders, such as collagen disease, diabetes or developmental anomalies in urogenital systems, were excluded. Individuals who had no detectable proteinuria on quantitative urinalysis were considered ‘unaffected’.

Genotyping and linkage analysis
The blood samples were collected from a total of 68 (28 affected and 40 unaffected) family members according to the protocol approved by the Ethics Review Committee. Family members were genotyped with at least four consecutive microsatellite markers spanning the critical regions, positioned 15–22 centiMorgans (cM) on either side of each locus [23]. Genotyping was performed using a fluorescence-labelled primer, and the DNA fragments were analysed using an ABI PRISM 377 DNA Sequencer. We calculated multipoint Logarithm of the odds (LOD) scores with the GENEHUNTER programme version 2.1 in the parametric model assuming autosomal recessive transmission with 100% penetrance, no phenocopy and disease gene frequency of 0.0001 [24,25]. Haplotypes were constructed by visual inspection in order to produce the most likely linkage phase by minimizing the number of recombinant events (Supplementary Figure 1).

Mutational analysis
Direct sequencing was performed using the DyeDeoxy Terminator method with an ABI PRISM 3100 capillary DNA Sequencer. We created primers flanking eight coding exons of NPHS2 according to the publicly available genomic sequence of the Bacterial Artificial Chromosomes (BAC) construct (GenBank AL160286 [GenBank] ) [11]. The primers for NPHS1 and NEPH1 were designed using their published cDNA sequences (AF035835 [GenBank] , AY302131 [GenBank] ) and the human genome database [10,14]



   Results
Top
 Introduction
 Subjects and methods
 Results
Discussion
 Acknowledgements
 References
 
Clinical phenotype of SRNS families
The clinical findings of the 15 Asian multiplex families are summarized in Table 1. Thirty-one patients presented with high-grade proteinuira at an average age of 44.4 months (range 6–132 months). The differences in the age of onset between the affected siblings did not exceed 2 years with the exception of SRNS-6, where two patients manifested the disease 7 years (Supplementary Figure 2). Spearman rank correlation coefficient (rs) for two ranks, defined as the first and second patients, respectively, yielded a value of 0.86. The result was significant on the 1% level, suggesting a strong intra-familial concordance regarding the age of onset. None of the parents currently had proteinuria, suggesting the autosomal recessive inheritance mode of transmission. Among the 27 patients who underwent renal biopsy, 25 were diagnosed with FSGS and the other two were diagonosed with MCNS. Light microscopy revealed mild mesangial proliferation, interstitial alteration and segmentally sclerosed glomeruli (data not shown). Transmission electron microscopy demonstrated mild podocyte foot process effacement without apparent ultrastructural changes of the glomerular basement membrane such as splitting, lamellation and fragmentation (data not shown). These findings were compatible with the histological diagnosis of FSGS. Twenty-two of 31 patients (~60%) progressed to ESRD at an average age of 6.1 years (range 8 months–16 years) and the mean time from initial presentation to the development of ESRD was 2.6 years (range 2 months–8 years). Thirteen of 22 ESRD patients (59%) who underwent a renal transplant have been free of recurrence to date, suggesting that the cause of proteinuria is intrinsic to the kidney. The remaining eight patients out of the total 31, maintained normal renal function over a median of 9 years during the follow-up period (range 2.3–16.0 years). These patients exhibited resistance to the initial course of standard steroid therapy, but thereafter partially responded to treatment including immunosuppressants of ciclosporin and cyclophosphamide. Notably, both the affected children in SRNS-3 and SRNS-7 presented with a less severe form of the illness and remitted after steroid therapy. In summary, the clinical courses regarding the age of onset and the progression of illness in the 15 SRNS families were consistent with those reported previously for SRNS patients (Table 2) [16–18].


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  		Table 1. Clinical characteristics of SRNS patients

 

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  		Table 2. Summary of clinical phenotypes of SRNS patients and NPHS2 mutations

 
Linkage analysis for the candidate genes
We first assessed the linkage to NPHS1 by haplotype inspection, demonstrating that nine out of 15 families had recombinant (non-linkage) haplotypes within the disease interval (Supplementary Figure 1). Calculation of the LOD scores and simulation analysis supported the conclusion that these families had non-linkage (data not shown). The remaining six families SRNS-2, SRNS-3, SRNS-8, SRNS-11, SRNS-14 and SRNS-15 displayed haplotypes that possibly segregate with the disease. In order to exclude the involvement of NPHS1 gene for this subgroup, we sequenced the entire 29 coding exons and found only several known Single Nucleotide Polymorphisms (SNPs) (Supplementary Table 1), thereby concluding that NPHS1 is not responsible in any of the 15 SRNS families.

We next tested whether the families are linked to the NPHS2 locus. Upon the haplotype inspection (Supplementary Figure 1), 11 families had recombinant haplotypes. The remaining four families SRNS-6, SRNS-7, SRNS-12 and SRNS-14, exhibited haplotypes segregating with the disease. We therefore sequenced all eight exons of NPHS2 for SRNS-6, SRNS-7, SRNS-12 and SRNS-14 and found only two previously reported SNPs (Supplementary Table 1), indicating that NPHS2 is not responsible for SRNS in any of the 15 families.

Similar analysis for NEPH1 locus revealed that it is not responsible for SRNS in any of the 15 families. Thus, the present data indicate that the three candidate loci NPHS1, NPHS2 and NEPH1 are not responsible for SRNS in the present 15 families, suggesting existence of non-allelic heterogeneity and ethnic difference of SRNS.



   Discussion
Top
 Introduction
 Subjects and methods
 Results
 Discussion
Acknowledgements
 References
 
In the present study, overall clinical features of our series, including age of onset, progression to ESRD, histological presentation and post-transplant outcome were compatible with those of sporadic/familial SRNS reported in previous studies with the patients of a Central Europe, North Africa and Middle East origin (Table 2). A striking finding in our study is the lack of contribution of NPHS1, NPHS2 and NEPH1 genes in 15 Asian families. The choice for recruitment and phenotypic restriction of the patients is crucial in order to reduce genetic heterogeneity and increase the detectable chance of any particular locus. We, therefore, focused on the Japanese and Korean population that have emerged from a relatively limited number of founders and are, therefore, potentially less allelic and locus heterogeneity for the same phenotypes. The patients from familial SRNS originally described by Fuchshuber et al. [7], typically had heavy proteinuria in the first year of their life (range 3 months–5 years) and reached ESRD before the age of 10 years. Recent reports demonstrated that even patients bearing NPHS1 and NPHS2 mutations had occasionally post-transplant recurrence [26,27], suggesting that we should broaden the ascertainment criteria so as to include the cases of recurrent SRNS after renal transplant. Our patients had an onset of proteinuria at an average age of 44 months, but ~60% of the affected individuals developed ESRD at the mean age of 6.1 years (Table 1), of which the phenotypic characteristics were principally compatible with those of familial SRNS originally reported.

Despite such similarity of clinical features, we found a substantial difference in frequency of NPHS1 and NPHS2 mutations. The results are in sharp contrast with those of European studies, suggesting that genetic factors of FSGS differ between Asian and Caucasian patients and that as yet unidentified genes are involved in the pathogenesis of SRNS in Asian patients. The Fin-major (nt 121 del CT) and Fin-minor (R1109X) alleles of NPHS1 are highly prevalent with allelic frequencies of 65 and 15%, respectively in CNF patients and the overall carrier frequencies are about 1.7 and 0.05% in the Finnish population, respectively [28]. Large-scale mutational studies of SRNS of various ethnic origins [16–18,29] revealed the NPHS2 mutations in 26–38% of multiplex families, and in 10.5–23% of sporadic cases, indicating that the NPHS2 mutants are broadly distributed throughout European and Middle East Countries (Table 2). Furthermore, in a study with the populations of multi-ethnic origin, the NPHS2 variant R229Q was prevalent in normal Caucasian and South American subjects, with an estimated frequency of 3–4% [16,30], suggesting that certain NPHS2 variants may act as a common susceptibility gene for proteinuria. Taken together with the previous data of the lack of NPHS2 mutations in 36 sporadic Japanese SRNS cases, our present data underscore the significant ethnic variation in SRNS disease alleles. Our results excluded the involvement of the NEPH1 gene in our families. Given slit membrane integrity is maintained by interaction of various podocyte proteins, other slit membrane genes, such as FAT-1 [31], may be potential candidates. Verification for the pathological significance of the other candidate genes must await further study.

One of the challenging issues in human genetic research is how to map and identify the disease gene in small recessive nuclear families. To overcome the problems, population isolates have been used with success to identify Mendelian disease genes [32]. Our study, recruiting the patients from two neighbouring countries in Asia, would take advantage of gene mapping [32]. Recent studies of population genetics with analyses of Y chromosome haplotypes and mitochondria DNA polymorphism revealed that the Japanese and the Koreans are originated from closely related lineages [33]. The Japanese, genetically isolated founder populations similar to that of Finland, originated from the founding groups of perhaps 1000 individuals who existed ~100 generations ago, may have advantages in mapping genes based on linkage disequilibrium [32], because there is a tendency for the patients to share ancestral haplotypes derived from a handful of founders. We are currently attempting to identify more SRNS families for a full-scale genome search and linkage disequilibrium mapping.

Supplementary data: Supplementary figures and tables can be found at NDT online.



   Acknowledgements
Top
 Introduction
 Subjects and methods
 Results
 Discussion
 Acknowledgements
References
 
We wish to thank all the family members who participated in this study. We are grateful to Dr Kimiko Nakagawa (Osaka Kaisei Hospital, Osaka), Dr Hisashi Kaneda (Toyama City Hospital, Toyama), Dr Sakurako Hoshii (National Nishi Sapporo Hospital, Sapporo), Dr Toshiyuki Itoh (Matsuyama Red Cross Hospital, Matsuyama) and Dr Yoshimitsu Gotoh (Nagoya Daini Red Cross Hospital, Nagoya) for assessing families, and to all who participated in this study. This work was supported by research grants from the Japanese Ministry of Education, Culture, Sports, Science and Technology (Human Genome Science), by a grant from the Uehara Memorial Life Science Foundation, by a Health and Labour Sciences Research Grant (H16-Kodomo-015) by Grant in Aid for Scientific Research B 16390245 and C 14571026 from Japan Society for the Promotion of Science and by a Grant for Child Health and Development (16C-2) from the Japanese Ministry of Health, Labour and Welfare. Part of this article was presented in abstract form at the Annual Society of Nephrology meeting, 2003. URL for data in this article are as follows: Online Mendelian Inheritance in Man (OMIM), http://www.ncbi.nlm.nih.gov/, UCSC Genome Browser, http://genome.ucsc.edu, Marshfield Center for Medical Genetics (http://research.marshfieldclinic.org/genetics/).

Conflict of interest statement. None declared.



   Notes
 
* The authors wish it to be known that, in their opinion, the first three authors contributed equally to this work. Back



   References
Top
 Introduction
 Subjects and methods
 Results
 Discussion
 Acknowledgements
 References
 

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Received for publication: 12. 4.06
Accepted in revised form: 18. 5.06


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K. Aya, J. Shimizu, Y. Ohtomo, K. Satomura, H. Suzuki, K. Yan, Y. Sado, T. Morishima, and H. Tanaka
NPHS1 gene mutation in Japanese patients with congenital nephrotic syndrome
Nephrol. Dial. Transplant., August 1, 2009; 24(8): 2411 - 2414.
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