Steroid-resistant nephrotic syndrome with mutations in NPHS2 (podocin): report from a three-generation family

Jain, Vani; Feehally, John; Jones, G R; Robertson, Lisa; Nair, Dheepa; Vasudevan, Pradeep

doi:10.1093/ckj/sfu028

Cited by 6 publications

(3 citation statements)

References 22 publications

(42 reference statements)

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“…Although the NPHS2 p.V260E variant likely arose in Africans, it was rst identi ed in several consanguineous families from the previous Omani empire [18,41,42] . Like the European founder variant p.R138Q, the p.V260E variant disrupts the transport of the modi ed podocin protein from the endoplasmic reticulum to the plasma membrane [43][44][45] .…”

Section: Genotype-phenotype Associationsmentioning

confidence: 99%

Causal and Putative Pathogenic Mutations Identified in 38.6% of Children with Primary SRNS in South Africa

Nandlal

Winkler

Bhimma

et al. 2022

Preprint

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The aim was to identify causal mutations in genes implicated in steroid resistant nephrotic syndrome (SRNS) within a South African population. We enrolled 119 children with primary NS; 71 SRNS and 48 steroid-sensitive NS. All children with SRNS underwent kidney biopsy. We first genotyped the NPHS2 gene for the p.V260E variant in all NS cases (n= 119) and controls (n= 219). To further identify additional variants, we performed whole-exome sequencing and interrogated ten genes (NPHS1, NPHS2, WT1, LAMB2, ACTN4, TRPC6, INF2, CD2AP, PLCE1, MYO1E) implicated in SRNS/FSGS in 56 SRNS cases and 29 controls; we also performed exome sequencing on two patients carrying the NPHS2 p.V260E mutation as positive controls. The overall detection rate of pathogenic mutations in children with SRNS was 27/70(38.57%): 15(21.43%) carried the NPHS2 p.V260E mutation and 12(17.14%) carried a pathogenic mutation in the heterozygous state in INF2 (n=8), CD2AP (n=3) or TRPC6 (n=1) genes. NPHS2 p.V260E homozygosity was specifically associated with biopsy-proven FSGS, accounting for 23.81% of Black children (15 of 63) with SR-FSGS. No causal mutations were identified in NPHS1, WT1, LAMB2, PLCE1, MYO1E and ACTN4. We report four novel variants in INF2, PLCE1, ACTN4 and TRPC6.Conclusion: The NPHS2 p.V260E mutation is a prevalent cause of SR-FSGS among Black South African children occurring in 23.81% of children with SRNS. Screening all Black African children presenting with NS for NPHS2 p.V260E will provide a precision diagnosis of SR-FSGS and inform clinical management.

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Section: Genotype-phenotype Associationsmentioning

confidence: 99%

Causal and Putative Pathogenic Mutations Identified in 38.6% of Children with Primary SRNS in South Africa

Nandlal

Winkler

Bhimma

et al. 2022

Preprint

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“…Thirty-nine variants, among them 25 missenses, four nonsenses, three splice-sites, four frameshifts, and three in the promoter region were published from June 2013 to February 2017 in a total of 109 out of 829 SRNS patients in many countries: China (Wang et al, 2017) [ 28 ]; India (Jaffer et al, 2014; Dhandapani et al 2017; Ramanathan et al 2017) [ 29 – 31 ]; Italy (Benetti et al, 2013) [ 32 ]; Iran (Basiratnia et al, 2013) [ 33 ]; United Kingdom (Jain et al, 2014) [ 34 ]; United States of America (Laurin et al, 2014; Phelan et al, 2015) [ 35 , 36 ]; Poland (Kuleta et al, 2014) [ 37 ]; Finland (Suvanto et al, 2016) [ 38 ]; Saudi Arabi (Kari et al, 2013) [ 39 ]; Japan (Ogino et al, 2015) [ 40 ]; Mexico (Carrasco-Miranda et al, 2013) [ 41 ]; Chile (Azocar et al, 2016) [ 42 ]; and Brazil (Guaragna et al, 2015) [ 43 ]. Ten out of those 39 mutations were unique and had not been annotated in public HGMD ( http://www.hgmd.cf.ac.uk/ac/index.php ) or in GnomeAD Browser ( http://gnomad.broadinstitute.org ) or in the Leiden Open Variation Database ( https://www.lovd.nl/NPHS2 ): six were missenses, three were located in splice-site regions, and two were frameshifts ( Table 1 ).…”

Section: Nphs2 Mutations Overviewmentioning

confidence: 99%

NPHS2Mutations: A Closer Look to Latin American Countries

Guaragna

Lutaif

Maciel‐Guerra

et al. 2017

BioMed Research International

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Nephrotic syndrome is one of the most common kidney pathologies in childhood, being characterized by proteinuria, edema, and hypoalbuminemia. In clinical practice, it is divided into two categories based on the response to steroid therapy: steroid-sensitive and steroid resistant. Inherited impairments of proteins located in the glomerular filtration barrier have been identified as important causes of nephrotic syndrome, with one of these being podocin, coded by NPHS2 gene. NPHS2 mutations are the most frequent genetic cause of steroid resistant nephrotic syndrome. The aim of this review is to update the list of NPHS2 mutations reported between June 2013 and February 2017, with a closer look to mutations occurring in Latin American countries.

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“…Jain et al reported a non-consanguineous family with three generations of individuals who were either compound heterozygotes for mutations in NPHS2 (R138Q and Q215X) or who have inherited a mutation and a non-neutral polymorphism (R229Q) [10]. The father and the daughter had a childhood onset SRNS.…”

Section: Podocin (Nphs2)mentioning

confidence: 99%

Steroid Resistant Nephrotic Syndrome-Genetic Consideration

Tasić

Gucev

Polenakovič

2015

Prilozi

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Nephrotic syndrome is defined as the association of massive proteinuria, hypoalbuminaemia, edema, and hyperlipidemia. It is separated to steroid-sensitive or steroid-resistant (SRNS) forms in respect to the response to intensive steroid therapy. SRNS usually progresses to end-stage renal failure. According to the North American Pediatric Renal Trials and Collaborative Studies SRNS constitutes the second most frequent cause of ESRD in the first two decades of life. Unfortunately, there is no curative treatment for majority of patients. Majority of the SRNS patients have the histologic picture of focal segmental glomerulosclerosis. Interestingly, the risk of recurrence in the kidney graft in patients with hereditary SRNS is lower than in those who do not have genetic background. The etiology and pathogenesis of SRSN has remained enigma for decades. The discovery of 39 dominant or recessive SRNS genes enabled better understanding of the function of the glomerular podocytes and slit membrane. Hildebrandt's group has shown that 85% of the SRNS cases with onset by 3 months of age and 66% with onset by 1 year of age can be explained by recessive mutations in one of four genes only (NPHS1, NPHS2, LAMB2, or WT1). The same group used modern diagnostic techniques such as the next generation sequencing and tested a large international cohort of SRNS patients (n = 1783 families). The diagnostic panel included 21 genes with a recessive mode of inheritance and 6 genes with a dominant mode of inheritance. Single-gene cause was detected in 29.5% (526 of 1783) of the families with SRNS that manifested before 25 years of age. The identification of causative single-gene mutations may have important therapeutic consequences in some cases. This is very important for patients who carry mutations in a gene of coenzyme Q10 biosynthesis (COQ2, COQ6, ADCK4, or PDSS2). In these patients the treatment with coenzyme Q10 may be indicated. Also, patients with recessive mutations in PLCE1 may respond fully to the treatment with steroids or cyclosporine A. The patients with CUBN may benefit the treatment with vitamin B12. The detection of causative mutations may also be very important for familial genetic counseling and for prenatal diagnosis.

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Steroid-resistant nephrotic syndrome with mutations in NPHS2 (podocin): report from a three-generation family

Cited by 6 publications

References 22 publications

Causal and Putative Pathogenic Mutations Identified in 38.6% of Children with Primary SRNS in South Africa

Causal and Putative Pathogenic Mutations Identified in 38.6% of Children with Primary SRNS in South Africa

NPHS2Mutations: A Closer Look to Latin American Countries

Steroid Resistant Nephrotic Syndrome-Genetic Consideration

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