TRPC6 mutational analysis in a large cohort of patients with focal segmental glomerulosclerosis

Santín, Sheila; Ars, Elisabet; Rossetti, Sandro; Salido, Eduardo; Silva, Irene; García-Maset, Rafael; Giménez, Isabel; Ruíz, Patricia; Mendizábal, Santiago; Gálvez-Nieto, José Luis; Pena, A De La; Camacho, Juan Antonio; Fraga, Gloria; Cobo, Ma Ángeles; Bernis, Carmen; Ortíz, Alberto; Pablos, Augusto Luque de; Sánchez-Moreno, Ana; Pintos, Guillem; Mirapeix, E; Fernández-Llama, Patricia; Ballarín, José; Torra, Roser

doi:10.1093/ndt/gfp229

Cited by 101 publications

(78 citation statements)

References 26 publications

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“…The high percentage of NPHS2 missense variants represents a diagnostic challenge because in some cases it is difficult to differentiate between a disease-causing mutation and a neutral variant. We describe here an in silico sequence variant classification strategy for the NPHS2 amino acid substitutions based on the combination of different approaches previously reported for other genes (30,41,42), which takes into account (1) the analysis of control chromosomes, (2) the cosegregation with the disease in a family, (3) the biophysical and biochemical difference between wild-type and mutant amino acids (28), (4) the evolutionary conservation of the amino acid residue in orthologs (29,43,44), and (5) software that uses in silico predictors of pathogenic effect [Polyphen (45), SIFT (46)] and splice site [Neural Network (47)]. The accuracy of this in silico analysis was tested using previously described and classified podocin-amino acid substitutions.…”

Section: Discussionmentioning

confidence: 99%

Clinical Value of NPHS2 Analysis in Early- and Adult-Onset Steroid-Resistant Nephrotic Syndrome

Santín

Tazón-Vega

Silva

et al. 2011

Clinical Journal of the American Society of Nephrology

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SummaryBackground and objectives To date, very few cases with adult-onset focal segmental glomerulosclerosis (FSGS) carrying NPHS2 variants have been described, all of them being compound heterozygous for the p.R229Q variant and one pathogenic mutation.Design, setting, participants, & measurements Mutation analysis was performed in 148 unrelated Spanish patients, of whom 50 presented with FSGS after 18 years of age. Pathogenicity of amino acid substitutions was evaluated through an in silico scoring system. Haplotype analysis was carried out using NPHS2 single nucleotide polymorphism and microsatellite markers.Results Compound heterozygous or homozygous NPHS2 pathogenic mutations were identified in seven childhood-onset steroid-resistant nephrotic syndrome (SRNS) cases. Six additional cases with late childhood-and adult-onset SRNS were compound heterozygotes for p.R229Q and one pathogenic mutation, mostly p.A284V. p.R229Q was more frequent among SRNS cases relative to controls (odds ratio ϭ 2.65; P ϭ 0.02). Significantly higher age at onset of the disease and slower progression to ESRD were found in patients with one pathogenic mutation plus the p.R229Q variant in respect to patients with two NPHS2 pathogenic mutations.Conclusions NPHS2 analysis has a clinical value in both childhood-and adult-onset SRNS patients. For adult-onset patients, the first step should be screening for p.R229Q and, if positive, for p.A284V. These alleles are present in conserved haplotypes, suggesting a common origin for these substitutions. Patients carrying this specific NPHS2 allele combination did not respond to corticoids or immunosuppressors and showed FSGS, average 8-year progression to ESRD, and low risk for recurrence of FSGS after kidney transplant.

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Section: Discussionmentioning

confidence: 99%

Clinical Value of NPHS2 Analysis in Early- and Adult-Onset Steroid-Resistant Nephrotic Syndrome

Santín

Tazón-Vega

Silva

et al. 2011

Clinical Journal of the American Society of Nephrology

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“…TRPC6, encodes a transient receptor potential cation channel and was originally identified as causing autosomal dominant FSGS, presenting in adolescence and early adulthood and showing relatively rapid progression to ESRD. Since then, TRPC6 mutations have been implicated in childhood-onset FSGS, and even SRNS presenting within the first year of life, with variable disease severity [8,10,77,79,80]. Similarly, mutations in ACTN4, which encodes alphaactinin 4, typically cause late-onset FSGS with slow progression to ESRD [29,81], but mutations in this gene have been reported in children presenting with SRNS and rapid progression to ESRD [8,82].…”

Section: Late-onset Nsmentioning

confidence: 99%

Genetic testing in steroid-resistant nephrotic syndrome: why, who, when and how?

2017

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Steroid-resistant nephrotic syndrome (SRNS) is a common cause of chronic kidney disease in childhood and has a significant risk of rapid progression to end-stage renal disease. The identification of over 50 monogenic causes of SRNS has revealed dysfunction in podocyte-associated proteins in the pathogenesis of proteinuria, highlighting their essential role in glomerular function. Recent technological advances in high-throughput sequencing have enabled indication-driven genetic panel testing for patients with SRNS. The availability of genetic testing, combined with the significant phenotypic variability of monogenic SRNS, poses unique challenges for clinicians when directing genetic testing. This highlights the need for clear clinical guidelines that provide a systematic approach for mutational screening in SRNS. The likelihood of identifying a causative mutation is inversely related to age at disease onset and is increased with a positive family history or the presence of extra-renal manifestations. An unequivocal molecular diagnosis could allow for a personalised treatment approach with weaning of immunosuppressive therapy, avoidance of renal biopsy and provision of accurate, well-informed genetic counselling. Identification of novel causative mutations will continue to unravel the pathogenic mechanisms of glomerular disease and provide new insights into podocyte biology and glomerular function.

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“…For example, Q889K, M132T, L780P, H218L, and R895L variants of TRPC6 have been identified in different populations, including FSGS and SRNS (15)(16)(17)(18). However, the prevalence of TRPC6 mutations and the genotype/phenotype correlation in pediatric INS in China have not been illustrated.…”

Section: Discussionmentioning

confidence: 99%

“…Until now, 13 TRPC6 mutations have been identified in 9 pedigrees (British, African American, Mexico, Irish/German, European/ Indian, Western European, Turkish, and Italian) and sporadic cases of FSGS (Spanish, Turkish, and Italian). Patients carrying TRPC6 mutations seem to progress to end-stage renal failure within 10 y (8,(14)(15)(16)(17)(18). However, the epidemiologic features of TRPC6 variants in Chinese pediatric INS have not yet been explored.…”

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confidence: 99%

254C>G: a TRPC6 promoter variation associated with enhanced transcription and steroid-resistant nephrotic syndrome in Chinese children

Kuang

Huang

et al. 2013

Pediatr Res

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Background: Mutations in canonical transient receptor potential channel 6 (TRPC6) have been identified as responsible for the development of focal segmental glomerulosclerosis, a proteinuric disease with steroid resistance and poor prognosis. This study explores the prevalence of TRPC6 variants in Chinese children with idiopathic nephrotic syndrome (INS), the genotype/phenotype correlation of TRPC6 variants, the therapeutic response, and the underlying molecular mechanism. Methods: Fifty-one children with sporadic INS were enrolled: 23 steroid-sensitive cases and 28 steroid-resistant cases. Polymerase chain reaction was used to amplify 13 exons and the promoter sequences of TRPC6 before sequencing. The expression of TRPC6 in renal tissues was illustrated by immunohistochemistry staining. The transcriptional activity of variants in TRPC6 promoter was measured by the luciferase assay. results: Three variants (-254C>G, rs3824934; +43C/T, rs3802829; and 240 G>A, rs17096918) were identified. The allele frequency of the -254C>G single-nucleotide polymorphism (SNP) in the steroid-resistant nephrotic syndrome (SRNS) patients (40.5%) was higher than that in the steroid-sensitive nephrotic syndrome subjects (27.1%; P = 0.046). The -254C>G SNP enhanced transcription from TRPC6 promoter in vitro and was associated with increased TRPC6 expression in renal tissues of SRNS patients. conclusion: -254C>G, a SNP underlying enhanced TRPC6 transcription and expression, may be correlated with the development of steroid resistance in Chinese children with INS.

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TRPC6 mutational analysis in a large cohort of patients with focal segmental glomerulosclerosis

Abstract: We describe for the first time TRPC6 mutations in children and adults with non-familial FSGS. It seems that TRPC6 is a gene with a very variable penetrance that may contribute to glomerular diseases in a multi-hit setting.

Cited by 101 publications

References 26 publications

Clinical Value of NPHS2 Analysis in Early- and Adult-Onset Steroid-Resistant Nephrotic Syndrome

Clinical Value of NPHS2 Analysis in Early- and Adult-Onset Steroid-Resistant Nephrotic Syndrome

Genetic testing in steroid-resistant nephrotic syndrome: why, who, when and how?

254C>G: a TRPC6 promoter variation associated with enhanced transcription and steroid-resistant nephrotic syndrome in Chinese children

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