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Specific podocin mutations determine age of onset of nephrotic syndrome all the way into adult life

2009; Elsevier BV; Volume: 75; Issue: 7 Linguagem: Inglês

10.1038/ki.2008.693

1523-1755

Friedhelm Hildebrandt, Saskia F. Heeringa,

Autoimmune Bullous Skin Diseases

In steroid-resistant nephrotic syndrome (SRNS) Machuca et al. report that mutations of the recessive podocin gene cause adult-onset SRNS if the R229Q genetic variant occurs in a compound heterozygous state with another podocin mutation. Learning to tell apart the specific allele combinations of podocin mutations will be important for prognosis, genetic counseling in living related kidney donation, accurate etiologic classification within treatment studies, and the understanding of podocin function. In steroid-resistant nephrotic syndrome (SRNS) Machuca et al. report that mutations of the recessive podocin gene cause adult-onset SRNS if the R229Q genetic variant occurs in a compound heterozygous state with another podocin mutation. Learning to tell apart the specific allele combinations of podocin mutations will be important for prognosis, genetic counseling in living related kidney donation, accurate etiologic classification within treatment studies, and the understanding of podocin function. Steroid-resistant nephrotic syndrome (SRNS), which typically manifests histologically as focal segmental glomerulosclerosis (FSGS), remains one of the most intractable kidney diseases. In children it carries a 30% risk of recurrence in a kidney transplant. Following identification of the podocin gene (NPHS2),1..Boute N. Gribouval O. Roselli S. et al.NPHS2, encoding the glomerular protein podocin, is mutated in autosomal recessive steroid-resistant nephrotic syndrome.Nat Genet. 2000; 24: 349-354Crossref PubMed Scopus (1198) Google Scholar it came as somewhat of a surprise to the nephrology community that 10–28% of all nonfamilial childhood cases of SRNS are caused by recessive podocin mutations as the single sufficient cause of the disease.2..Karle S.M. Uetz B. Ronner V. et al.Novel mutations in NPHS2 detected in both familial and sporadic steroid-resistant nephrotic syndrome.J Am Soc Nephrol. 2002; 13: 388-393PubMed Google Scholar (The term 'recessive mutations' refers to the fact that mutations in both parental podocin alleles have been detected in the patient and are necessary and sufficient for disease manifestation.) Furthermore, an important correlation between genotype and treatment response was revealed in the finding that patients with two recessive mutations of the podocin gene do not respond to standard steroid treatment but on the other hand have a strongly reduced likelihood of FSGS recurrence in a renal transplant (35% versus 8%).3..Ruf R.G. Lichtenberger A. Karle S.M. et al.Patients with mutations in NPHS2 (podocin) do not respond to standard steroid treatment of nephrotic syndrome.J Am Soc Nephrol. 2004; 15: 722-732Crossref PubMed Scopus (374) Google Scholar, 4..Weber S. Gribouval O. Esquivel E.L. et al.NPHS2 mutation analysis shows genetic heterogeneity of steroid-resistant nephrotic syndrome and low post-transplant recurrence.Kidney Int. 2004; 66: 571-579Abstract Full Text Full Text PDF PubMed Scopus (305) Google Scholar These findings are clinically quite relevant. They allow for an etiology-based disease classification of SRNS/FSGS, as the recessive mutations embody the primary cause of the disease. In other words, a mutation in a single gene alone is sufficient to cause disease in a given patient, although different 'single-gene,' or 'monogenic,' causes may be active in different patients. Thus, recessive disease genes probably represent the most cogent basis for 'genetic personalized medicine,' based on their full penetrance (that is, a patient who carries two podocin mutations will develop FSGS with near certainty). In addition, with very few exceptions,5..Hinkes B. Wiggins R.C. Gbadegesin R. et al.Positional cloning uncovers mutations in PLCE1 responsible for a nephrotic syndrome variant that may be reversible.Nat Genet. 2006; 38: 1397-1405Crossref PubMed Scopus (450) Google Scholar all monogenic forms of SRNS lead to end-stage kidney disease (ESKD). From the emerging list of monogenic causes of SRNS, it soon became apparent that there is a strong correlation between the causative gene mutations and the age of onset of FSGS or ESKD, in at least two ways (Figure 1): First, mutations in different genes manifest with SRNS at different ages. Specifically, recessive genes that cause SRNS, including nephrin (NPHS1), podocin (NPHS2), laminin-β2 (LAMB2), and phospholipase C-ε1 (PLCE1), lead to childhood-onset SRNS, whereas the extremely rare mutations in dominant genes, including actinin-α4 (ACTN4) and TRPC6, cause adult-onset disease (Figure 1).6..Tryggvason K. Patrakka J. Wartiovaara J. Hereditary proteinuria syndromes and mechanisms of proteinuria.N Engl J Med. 2006; 354: 1387-1401Crossref PubMed Scopus (444) Google Scholar, 7..Wiggins R.C. The spectrum of podocytopathies: a unifying view of glomerular diseases.Kidney Int. 2007; 71: 1205-1214Abstract Full Text Full Text PDF PubMed Scopus (579) Google Scholar (The genes CD2AP and WT1 represent somewhat of an exception to the rule.) In addition, the earlier the onset of SRNS, the more likely that it is of monogenic origin, as 85% of all SRNS manifesting in the first 3 months of life and 66% of all SRNS manifesting in the first year of life are caused by mutations in one of only four genes, nephrin, podocin, LAMB2, or WT1.8..Hinkes B.G. Mucha B. Vlangos C.N. et al.Nephrotic syndrome in the first year of life: two thirds of cases are caused by mutations in 4 genes (NPHS1, NPHS2, WT1, and LAMB2).Pediatrics. 2007; 119: e907-e919Crossref PubMed Scopus (357) Google Scholar Second, for recessive podocin mutations, the combination of the two parental alleles (that is, the specific mutation in each parental copy of the podocin gene) determines the age of onset of SRNS and ESKD.9..Hinkes B. Vlangos C. Heeringa S. et al.Specific podocin mutations correlate with age of onset in steroid-resistant nephrotic syndrome.J Am Soc Nephrol. 2008; 19: 365-371Crossref PubMed Scopus (121) Google Scholar Specifically, the presence of at least one mutation that truncates the protein (for example, a stop codon) together with one other mutation, or the presence of the mutation R138Q homozygously, leads to early onset of SRNS at a median age of 1.7 years. In contrast, the presence of two missense mutations causes later onset at a median of 4.7 years (Figure 1a and b).9..Hinkes B. Vlangos C. Heeringa S. et al.Specific podocin mutations correlate with age of onset in steroid-resistant nephrotic syndrome.J Am Soc Nephrol. 2008; 19: 365-371Crossref PubMed Scopus (121) Google Scholar The R138Q mutation is derived from a genetic founder in Western Europe. These findings revealed that podocin mutations are subject to 'multiple allelism,' in which the clinical severity or age of onset of disease varies by the specific nature and combination of the two mutations (alleles) that a patient carries. This is most clearly conveyed by the fact that specific alterations of the podocin protein result in different degrees of loss of function. Interestingly, complete loss of function of podocin may lead to such early manifestation that it interferes with glomerular development, leading to the morphologic phenotype of congenital nephrotic syndrome of the Finnish type (CNS-FT) rather than to FSGS (Figure 1c and d).8..Hinkes B.G. Mucha B. Vlangos C.N. et al.Nephrotic syndrome in the first year of life: two thirds of cases are caused by mutations in 4 genes (NPHS1, NPHS2, WT1, and LAMB2).Pediatrics. 2007; 119: e907-e919Crossref PubMed Scopus (357) Google Scholar The severity of the R138Q allele was confirmed in a knock-in mouse model of nephrotic syndrome, in which diffuse mesangial sclerosis (DMS) resulted.10..Philippe A. Weber S. Esquivel E.L. et al.A missense mutation in podocin leads to early and severe renal disease in mice.Kidney Int. 2008; 73: 1038-1047Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar This discovery demonstrated that the histologic distinctions of DMS, CNS-FT, and FSGS represent only intermediate phenotypes that may differ between patients on the basis of the specific allelic mutations of one and the same causative gene (Figure 1c).5..Hinkes B. Wiggins R.C. Gbadegesin R. et al.Positional cloning uncovers mutations in PLCE1 responsible for a nephrotic syndrome variant that may be reversible.Nat Genet. 2006; 38: 1397-1405Crossref PubMed Scopus (450) Google Scholar Within the spectrum of age-related onset determined by different podocin mutations, adult onset was rarely, if ever, seen (where adult onset is defined as onset of proteinuria after 18 years of life).11..He N. Zahirieh A. Mei Y. et al.Recessive NPHS2 (Podocin) mutations are rare in adult-onset idiopathic focal segmental glomerulosclerosis.Clin J Am Soc Nephrol. 2007; 2: 31-37Crossref PubMed Scopus (62) Google Scholar, 12..Ardiles L.G. Carrasco A.E. Carpio J.D. Mezzano S.A. Late onset of familial nephrotic syndrome associated with a compound heterozygous mutation of the podocin-encoding gene.Nephrology (Carlton). 2005; 10: 553-556Crossref PubMed Scopus (12) Google Scholar, 13..Monteiro E.J. Pereira A.C. Pereira A.B. et al.NPHS2 mutations in adult patients with primary focal segmental glomerulosclerosis.J Nephrol. 2006; 19: 366-371PubMed Google Scholar, 14..McKenzie L.M. Hendrickson S.L. Briggs W.A. et al.NPHS2 variation in sporadic focal segmental glomerulosclerosis.J Am Soc Nephrol. 2007; 18: 2987-2995Crossref PubMed Scopus (57) Google Scholar Machuca et al.15..Machuca E. Hummel A. Nevo F. et al.Clinical and epidemiological assessment of steroid-resistant nephrotic syndrome associated with the NPHS2 R229Q variant.Kidney Int. 2009; 75: 727-735Abstract Full Text Full Text PDF PubMed Scopus (117) Google Scholar (this issue) now demonstrate that recessive podocin mutations may also cause adult-onset SRNS if a certain kind of mutation is involved. The specific mutation, known as R229Q, may have gone unrecognized for some time because of its 'bland' nature. R229Q was previously considered by most to represent an 'innocuous polymorphism' of podocin because it occurs in 2–4% of healthy individuals. This assessment was based on a large meta-analysis16..Franceschini N. North K.E. Kopp J.B. et al.NPHS2 gene, nephrotic syndrome and focal segmental glomerulosclerosis: a HuGE review.Genet Med. 2006; 8: 63-75Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar and on a lack of clear evidence of a functional defect resulting from R229Q, although, early on, a potential genetic interaction between the R229Q variant of podocin and nephrin was described,17..Caridi G. Bertelli R. Di Duca M. et al.Broadening the spectrum of diseases related to podocin mutations.J Am Soc Nephrol. 2003; 14: 1278-1286Crossref PubMed Scopus (166) Google Scholar, 18..Koziell A. Grech V. Hussain S. et al.Genotype/phenotype correlations of NPHS1 and NPHS2 mutations in nephrotic syndrome advocate a functional inter-relationship in glomerular filtration.Hum Mol Genet. 2002; 11: 379-388Crossref PubMed Scopus (232) Google Scholar as well as the presence of compound heterozygous podocin mutations that included R229Q.19..Tsukaguchi H. Sudhakar A. Le T.C. et al.NPHS2 mutations in late-onset focal segmental glomerulosclerosis: R229Q is a common disease-associated allele.J Clin Invest. 2002; 110: 1659-1666Crossref PubMed Scopus (223) Google Scholar The distinction between a 'bona fide' mutation and an innocuous polymorphism is usually based on the findings that the former is absent from 100 healthy control individuals, can be demonstrated to be deleterious in an in vitro or in vivo assay or animal model, or leads to conceptual loss of function of the protein (for example, by introducing a premature stop codon, or changing an amino acid residue of the encoded protein that is highly conserved throughout evolution or changing it to a functionally very different residue). In the R229Q variant, none of these distinctions was conclusive. Machuca et al.15..Machuca E. Hummel A. Nevo F. et al.Clinical and epidemiological assessment of steroid-resistant nephrotic syndrome associated with the NPHS2 R229Q variant.Kidney Int. 2009; 75: 727-735Abstract Full Text Full Text PDF PubMed Scopus (117) Google Scholar systematically followed up on the initial evidence that R229Q might in fact not represent an innocuous polymorphism but might, when combined with a second bona fide podocin mutation, rather cause adult-onset SRNS as initially described by Tsukaguchi et al.19..Tsukaguchi H. Sudhakar A. Le T.C. et al.NPHS2 mutations in late-onset focal segmental glomerulosclerosis: R229Q is a common disease-associated allele.J Clin Invest. 2002; 110: 1659-1666Crossref PubMed Scopus (223) Google Scholar The authors here provide evidence that recessive podocin mutations may not be as rare in adult-onset SRNS as previously thought, although some groups described them as virtually absent.11..He N. Zahirieh A. Mei Y. et al.Recessive NPHS2 (Podocin) mutations are rare in adult-onset idiopathic focal segmental glomerulosclerosis.Clin J Am Soc Nephrol. 2007; 2: 31-37Crossref PubMed Scopus (62) Google Scholar, 12..Ardiles L.G. Carrasco A.E. Carpio J.D. Mezzano S.A. Late onset of familial nephrotic syndrome associated with a compound heterozygous mutation of the podocin-encoding gene.Nephrology (Carlton). 2005; 10: 553-556Crossref PubMed Scopus (12) Google Scholar, 13..Monteiro E.J. Pereira A.C. Pereira A.B. et al.NPHS2 mutations in adult patients with primary focal segmental glomerulosclerosis.J Nephrol. 2006; 19: 366-371PubMed Google Scholar, 14..McKenzie L.M. Hendrickson S.L. Briggs W.A. et al.NPHS2 variation in sporadic focal segmental glomerulosclerosis.J Am Soc Nephrol. 2007; 18: 2987-2995Crossref PubMed Scopus (57) Google Scholar, 20..Kottgen A. Hsu C.C. Coresh J. et al.The association of podocin R229Q polymorphism with increased albuminuria or reduced estimated GFR in a large population-based sample of US adults.Am J Kidney Dis. 2008; 52: 868-875Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar Machuca et al.15..Machuca E. Hummel A. Nevo F. et al.Clinical and epidemiological assessment of steroid-resistant nephrotic syndrome associated with the NPHS2 R229Q variant.Kidney Int. 2009; 75: 727-735Abstract Full Text Full Text PDF PubMed Scopus (117) Google Scholar sequenced the entire coding region of podocin in 455 patients from unrelated families with SRNS who had not responded to immunosuppressive therapy and who did not have post-transplantation recurrence. They found a significantly higher prevalence of the R229Q variant of podocin in European patients versus controls. The total cohort represented patients from Europe (55.2%), the Middle East (11.9%), North Africa (14.7%), South America (10.3%), and other regions (7.9%). The authors identified homozygous or compound heterozygous podocin mutations in 65 of 455 different families (14.3%). In addition, they detected 27 compound heterozygous individuals from different families (5.9% of all families examined) who carried a heterozygous R229Q variant with a bona fide podocin mutation (most of these mutations were missense mutations). Thirteen of these individuals were from Europe and 14 were from South America. The authors detected the following novel correlation between genotype and age of onset of SRNS: the patients with compound heterozygosity for the R229Q variant and a bona fide podocin mutation developed adult onset of SRNS at a median age of 19 years (and ESKD at 28 years), whereas the patients with two bona fide podocin mutations exhibited onset of SRNS in infancy or childhood with a median onset of SRNS at 1.1 years (and ESKD at 8 years) as described before for bona fide mutations. The notion that compound heterozygosity for the R229Q variant and a bona fide podocin mutation represents a prevalent adult-onset constellation of podocin mutations was confirmed by the authors' finding that among 119 patients who presented with SRNS after 18 years of age, 18 (15%) presented with this constellation, but none was found with two bona fide podocin mutations in this age group. Although these results would leave 85% of adult-onset cases unexplained by podocin mutations, the findings strongly suggest that the allelic constellation of compound heterozygosity for R229Q together with a bona fide podocin mutation represents a genetic finding characteristic of onset of SRNS in young adults. Mutations should consequently be investigated in these patients to better characterize this patient cohort in the future. Interestingly, R229Q was found relatively often in a compound heterozygous state with the A284 V mutation. Two of these patients were from Spain, and 13 were of Hispanic descent living in South America. It will be interesting to see whether the A284 V mutation occurs on a conserved haplotype introduced by a Spanish founder. Seeking specific R229Q/A284 V compound heterozygosity in patients of Spanish descent might help to better define the natural history and potential treatment responses of their SRNS. In five families in whom R229Q occurred homozygously in some individuals, there was incomplete penetrance, indicating the weak action of R229Q. This study also emphasizes that the functional significance of certain mutations such as R229Q in recessive diseases may be evaluated only in the context of the specific second mutation present in the compound heterozygous state. Learning to tell apart the different 'flavors' of specific allele combinations of podocin mutations will be very important for making a prognosis, for adequate genetic counseling and counseling for living related kidney donation, and for accurate etiologic classification within treatment studies, as well as for the understanding of podocin function. This work was supported by National Institutes of Health grant DK076683 to FH, who is an Investigator of the Howard Hughes Medical Institute, the Frederick GL Huetwell Professor, and a Doris Duke Distinguished Clinical Scientist, and by a grant from the Dutch Kidney Foundation to SFH.