Mutations in PLCE1 are a major cause of isolated diffuse mesangial sclerosis (IDMS)

Gbadegesin, Rasheed; Hinkes, Bernward; Hoskins, Bethan E.; Vlangos, Christopher N.; Heeringa, Saskia F.; Liu, Jinhong; Loirat, Chantal; Özaltın, Fatih; Hashmi, Seema; Ulmer, Francis; Cleper, Roxanna; Ettenger, Robert B.; Antignac, Corinne; Wiggins, Roger C.; Zenker, Martin; Hildebrandt, Friedhelm

doi:10.1093/ndt/gfm759

Cited by 140 publications

(85 citation statements)

References 23 publications

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“…In infantile onset and in childhood onset, we propose starting with the NPHS2 gene and, if no mutations are found, screening for NPHS1 in familial and sporadic cases and WT1 only in females with sporadic SRNS. Although we have not found pathogenic mutations in PLCE1 in early-onset SRNS, PLCE1 analysis would be indicated in those cases with familial DMS/FSGS (20,22 (37). Mutations in the TRPC6 gene have been found in 1 of 41 cases of sporadic adult-onset SRNS, being a rare cause of adult-onset FSGS.…”

Section: Discussionmentioning

confidence: 60%

Clinical Utility of Genetic Testing in Children and Adults with Steroid-Resistant Nephrotic Syndrome

Santín

Bullich

Tazón-Vega

et al. 2011

Clinical Journal of the American Society of Nephrology

197

172

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SummaryBackground and objectives The increasing number of podocyte-expressed genes implicated in steroid-resistant nephrotic syndrome (SRNS), the phenotypic variability, and the uncharacterized relative frequency of mutations in these genes in pediatric and adult patients with SRNS complicate their routine genetic analysis. Our aim was to compile the clinical and genetic data of eight podocyte genes analyzed in 110 cases (125 patients) with SRNS (ranging from congenital to adult onset) to provide a genetic testing approach.Design, setting, participants, & measurements Mutation analysis was performed by sequencing the NPHS1, NPHS2, TRPC6, CD2AP, PLCE1, INF2, WT1 (exons 8 and 9), and ACTN4 (exons 1 to 10) genes. ResultsWe identified causing mutations in 34% (37/110) of SRNS patients, representing 67% (16/24) familial and 25% (21/86) sporadic cases. Mutations were detected in 100% of congenital-onset, 57% of infantileonset, 24 and 36% of early and late childhood-onset, 25% of adolescent-onset, and 14% of adult-onset patients. The most frequently mutated gene was NPHS1 in congenital onset and NPHS2 in the other groups. A partial remission was observed in 7 of 26 mutation carriers treated with immunosuppressive agents and/or angiotensin-converting enzyme inhibitors. Patients with NPHS1 mutations showed a faster progression to ESRD than patients with NPHS2 mutations. None of these mutation carriers relapsed after kidney transplantation. ConclusionsWe propose a genetic testing algorithm for SRNS based on the age at onset and the familial/ sporadic status. Mutation analysis of specific podocyte-genes has a clinical value in all age groups, especially in children.

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Section: Discussionmentioning

confidence: 60%

Clinical Utility of Genetic Testing in Children and Adults with Steroid-Resistant Nephrotic Syndrome

Santín

Bullich

Tazón-Vega

et al. 2011

Clinical Journal of the American Society of Nephrology

197

172

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“…In the context of discovering and studying novel genes, about 400 of the 1783 families underwent Sanger sequencing for the rare genes PLCE1, LAMB2, SMARCAL1, INF2, COQ6, TRPC6, ITGA3, CUBN, ADCK4, and ARHGDIA. [17][18][19][20][21][22][23][24][25] Disease-causing mutations were detected in 170 families for NPHS2, 93 families for NPHS1, and 78 families for WT1. In an additional 51 families, causative mutations were detected in 1 of the other rare genes, thereby unveiling the causative mutation in a total of 392 families ( Table 1).…”

Section: Identification Of Causative Mutations In An International Srmentioning

confidence: 99%

A Single-Gene Cause in 29.5% of Cases of Steroid-Resistant Nephrotic Syndrome

Sadowski

Lovric

Ashraf

et al. 2015

Journal of the American Society of Nephrology

546

642

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Steroid-resistant nephrotic syndrome (SRNS) is the second most frequent cause of ESRD in the first two decades of life. Effective treatment is lacking. First insights into disease mechanisms came from identification of single-gene causes of SRNS. However, the frequency of single-gene causation and its age distribution in large cohorts are unknown. We performed exon sequencing of NPHS2 and WT1 for 1783 unrelated, international families with SRNS. We then examined all patients by microfluidic multiplex PCR and next-generation sequencing for all 27 genes known to cause SRNS if mutated. We detected a single-gene cause in 29.5% (526 of 1783) of families with SRNS that manifested before 25 years of age. The fraction of families in whom a single-gene cause was identified inversely correlated with age of onset. Within clinically relevant age groups, the fraction of families with detection of the single-gene cause was as follows: onset in the first 3 months of life (69.4%), between 4 and 12 months old (49.7%), between 1 and 6 years old (25.3%), between 7 and 12 years old (17.8%), and between 13 and 18 years old (10.8%). For PLCE1, specific mutations correlated with age of onset. Notably, 1% of individuals carried mutations in genes that function within the coenzyme Q 10 biosynthesis pathway, suggesting that SRNS may be treatable in these individuals. Our study results should facilitate molecular genetic diagnostics of SRNS, etiologic classification for therapeutic studies, generation of genotype-phenotype correlations, and the identification of individuals in whom a targeted treatment for SRNS may be available.

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“…Again, significant clinical heterogeneity exists, with PLCE1 mutations manifesting from birth and throughout childhood, with both FSGS or DMS found histologically [73,74].…”

Section: Infantile and Childhood 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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Mutations in PLCE1 are a major cause of isolated diffuse mesangial sclerosis (IDMS)

Cited by 140 publications

References 23 publications

Clinical Utility of Genetic Testing in Children and Adults with Steroid-Resistant Nephrotic Syndrome

Clinical Utility of Genetic Testing in Children and Adults with Steroid-Resistant Nephrotic Syndrome

A Single-Gene Cause in 29.5% of Cases of Steroid-Resistant Nephrotic Syndrome

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

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