NDT Advance Access originally published online on January 11, 2007
Nephrology Dialysis Transplantation 2007 22(5):1477-1479; doi:10.1093/ndt/gfl833
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Lack of cardiac anomalies in children with NPHS2 mutations
Email: labnefro{at}ospedale-gaslini.ge.itSir,
Podocin is an integral membrane protein of podocytes that interacts with nephrin and contributes to maintain the intact ultra-filtration barrier at the slit-diaphragm [1]. The discovery of mutations of NPHS2 (the gene encoding for podocin) in familial nephrotic syndrome [1] represented a breakthrough in the research of mechanisms of proteinuria that overcomes a pure genetic and clinical interest. NPHS2 mutations account for a significant proportion of all nephrotic patients, roughly corresponding to a mutation detection rate of 45–55% in families with recessive traits and 8–20% of sporadic cases, according to different cohorts and considering all the clinical phenotypes [2–5]. The recent report of an association of the NPHS2 founder mutation R138X with cardiac anomalies in six consanguineous Arabs [6] was unexpected, considering the kidney specificity of the protein. The cardiac defects described in carriers of R138X mutation mainly consisted in left ventricular hypertrophy (eight cases) followed by pulmonary stenosis (five cases), sub-aortic stenosis (two cases) and by septal defects. Overall, cardiac anomalies were detected in 18 out of 20 individuals (89%) and it was speculated, on this basis, that the cardiac phenotype resulted from NPHS2 mutation ‘per se’. The association of cardiac malformation with congenital nephrotic syndrome of the Finnish type is not new and the presence of pulmonary stenosis has been reported in a significant portion of these patients [7,8], who notably carry a mutation in NPHS1, the gene coding for nephrin that interacts with podocin in the slit diaphragm. Several observations are, however, against a true association of the cardiac defect with NPHS1 and/or NPHS2 mutations, rather suggesting a casual link: (i) there is a great consanguinity in the Arab pedigrees described by Frishberg, suggesting co-inheritance of two separate genetic defects; (ii) podocin, nephrin and related mRNAs are not expressed by adult heart and are only minimally detectable in fetal heart [1]; (iii) Nphs2–/– null mice do not develop clinically relevant cardiac anomalies [9], (iv) the four patients of the Arab cohorts who underwent renal transplant recovered normal heart anatomy and function [6].
It is clear that if podocin mutations are associated with heart defects, extensive cardiac evaluation and interplay with cardiologists must be considered in patients carrying NPHS2 defects, to achieve prevention of more advanced cardiac defects. Before considering this assumption as definitive, it is mandatory to confirm the association of cardiac defects in sporadic carriers of NPHS2 mutations.
We re-evaluated the clinical files and echocardiography evaluation of 12 patients with NPHS2 mutations and sporadic nephrotic syndrome and failed to confirm the association with cardiac defects. All patients enrolled in the study had developed proteinuria and nephrotic syndrome in the early decade of life and had presented with strict resistance to steroids (Table 1). With the exception of one patient (No. 2 in Table 1) who presented normal renal function, all had developed end-stage renal failure and had received a renal graft. According to prevalence of NPHS2 mutations in Europe [10], 419delG and R138Q were the two most frequent mutations found in our patient cohort, altogether accounting for 70% of the cases. The former determines a frameshift from glycine 140, with formation of a truncated protein. R138Q is a missense mutation at exon 3. Seven patients had an echocardiogram before the renal graft (patient 1 had two exams); these were normal in all cases with the exception of patients 5 and 6, who presented left ventricular hypertrophy (LVH). The former had a normal echocardiogram after the transplant procedure, while the latter still presented mild LVH at this stage. Six patients had an echocardiogram only after the graft. Only one child (No. 8) presented mild mitral insufficiency and the other five had a normal condition. Therefore, among the 12 patients studied here, 10 had a normal heart condition and two presented mild anomalies with mitral insufficiency and LVH in concomitance with normal arterial pressure. Overall, our data do not confirm the alarming results by Frishberg et al. [6]. In our cohort, a single patient presented the same mutation of the Arab families (R138X) that determine a truncated protein. However, the great majority of our patients presented the same 419delG mutation that also produce a truncate protein, and may be comparable with the above defect. Lack of heart defects in the majority of our patients lessens the likelihood of the podocin protein defect being associated with cardiac defects. We suggest re-evaluation of the association, because it cannot be excluded that in the Frishberg study group, one hitherto uncharacterized gene causing the heart defect has been co-inherited with NPHS2 [6].
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A new genetic approach in the Arab cohort could also lead to the definitive comprehension of the reason for the heart defect associated with nephrotic syndrome in this particular cohort, and form the basis for a characterization of new genes involved in familial heart defects.
Conflict of interest statement. None declared.
1Laboratory on
Pathophysiology of Uremia
Istituto G. Gaslini, Genova
2Renal Child Foundation, Genoa
3Nephrology Sections
Ospedale Bambin Gesù Roma
4Department of Nephrology
Dialysis and Transplantation
Ospedale Regina Margherita
Torino
5Section of Nephrology
Istituto G. Gaslini, Genova, Italy
References
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