Novel NPHS2 variant in patients with familial steroid-resistant nephrotic syndrome with early onset, slow progression and dominant inheritance pattern

Suvanto, Maija; Patrakka, Jaakko; Jahnukainen, Timo; Sjöström, Pia-Maria; Nuutinen, Matti; Arikoski, Pekka; Kataja, Janne; Kestilä, Marjo; Jalanko, Hannu

doi:10.1007/s10157-016-1331-3

Cited by 8 publications

(11 citation statements)

References 31 publications

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“…Otherwise, it would be an already known association (Table ). It is enriched (even non‐significantly) among patients with [p.R229Q];[mut] as compared with the patients with [mut];[mut], that is, a mutation of a novel p.R229Q association should not have been reported to be associated to another NPHS2 mutation in more than a single case in populations with frequent p.R229Q. The [p.R229Q];[mut] association segregates with the disease in the family. The associated phenotype corresponds to the p.R229Q‐associated nephropathy with no overt edema, FSGS on histology and low rate of progression (leading to ESRD between 10 and 50 years of age). The mutation is in trans with p.R229Q. Particular attention has to be paid to p.P341R, which was reported in the heterozygous state in a patient with homozygous p.R229Q (Suvanto et al., ), indicating that this mutation appeared on an p.R229Q allele. A patient with heterozygous p.R229Q and p.P341R is therefore primarily expected to carry these variants in cis.…”

Section: Pathogenic and Benign Pr229q Associationsmentioning

confidence: 99%

“…The mutation is in trans with p.R229Q. Particular attention has to be paid to p.P341R, which was reported in the heterozygous state in a patient with homozygous p.R229Q (Suvanto et al., ), indicating that this mutation appeared on an p.R229Q allele. A patient with heterozygous p.R229Q and p.P341R is therefore primarily expected to carry these variants in cis.…”

Section: Pathogenic and Benign Pr229q Associationsmentioning

confidence: 99%

Section: The Expected Frequency Of Individuals With [Pr229q];mentioning

confidence: 99%

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The mutation-dependent pathogenicity ofNPHS2p.R229Q: A guide for clinical assessment

Mikó

Menyhárd

Kaposi³

et al. 2018

Human Mutation

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NPHS2, encoding podocin, is the major gene implicated in steroid‐resistant nephrotic syndrome. Its c.686G>A, p.R229Q variant is the first human variant with a mutation‐dependent pathogenicity; it is only pathogenic when trans‐associated to specific mutations. Secondary to its high allele frequency in the European, South Asian, African, and Latino populations, its benign trans‐associations can be accidentally identified in affected patients. Distinguishing pathogenic and benign p.R229Q associations can be challenging. In this paper, we present the currently known pathogenic and benign associations, and show that a rare p.R229Q association can be considered pathogenic if the variant in trans meets the following criteria; it affects the 270–351 residues and alters but does not disrupt the oligomerization, its p.R229Q association is found in a family with slowly progressing focal segmental glomerulosclerosis, but is expected to be rare in the general population (<1:106). We show that >15% of the p.R229Q associations identified so far in patients are benign.

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Section: Pathogenic and Benign Pr229q Associationsmentioning

confidence: 99%

Section: Pathogenic and Benign Pr229q Associationsmentioning

confidence: 99%

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The mutation-dependent pathogenicity ofNPHS2p.R229Q: A guide for clinical assessment

Mikó

Menyhárd

Kaposi³

et al. 2018

Human Mutation

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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%

“…Two small deletions were described: one (p.Ser329 = fs ∗ 14) was found in heterozygosis in five SRNS individuals from the same Finnish family, with early-onset, slow progression, and dominant inheritance pattern [ 38 ]; the other (p.Lis239Argfs ∗ 13) was identified by our group in two Brazilian sisters with early-onset SRNS in association with the p.Val260Glu missense [ 43 ].…”

Section: Frameshift Mutationsmentioning

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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Identification of key biomarkers in diabetic nephropathy via bioinformatic analysis

Liu

Yang

et al. 2018

J of Cellular Biochemistry

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Diabetic nephropathy (DN) is a major cause of end‐stage renal disease. Although intense efforts have been made to elucidate the pathogenesis, the molecular mechanisms of DN remain to be clarified. To identify the candidate genes in the progression of DN, microarray datasets GSE30122, GSE30528, and GSE47183 were downloaded from the Gene Expression Omnibus database. The differentially expressed genes (DEGs) were identified, and function enrichment analyses were performed. The protein‐protein interaction network was constructed and the module analysis was performed using the Search Tool for the Retrieval of Interacting Genes and Cytoscape. A total of 61 DEGs were identified. The enriched functions and pathways of the DEGs included glomerulus development, extracellular exosome, collagen binding, and the PI3K‐Akt signaling pathway. Fifteen hub genes were identified and biological process analysis revealed that these genes were mainly enriched in acute inflammatory response, inflammatory response, and blood vessel development. Correlation analysis between unexplored hub genes and clinical features of DN suggested that COL6A3, MS4A6A,PLCE1, TNNC1, TNNI1, TNN2, and VSIG4 may involve in the progression of DN. In conclusion, DEGs and hub genes identified in this study may deepen our understanding of molecular mechanisms underlying the progression of DN, and provide candidate targets for diagnosis and treatment of DN.

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Novel NPHS2 variant in patients with familial steroid-resistant nephrotic syndrome with early onset, slow progression and dominant inheritance pattern

Abstract: The role of podocin variants in nephrotic syndrome may be more varied than previously thought.

Cited by 8 publications

References 31 publications

The mutation-dependent pathogenicity ofNPHS2p.R229Q: A guide for clinical assessment

The mutation-dependent pathogenicity ofNPHS2p.R229Q: A guide for clinical assessment

NPHS2Mutations: A Closer Look to Latin American Countries

Identification of key biomarkers in diabetic nephropathy via bioinformatic analysis

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