Dataset Information

Recessive Mutations in SYNPO2 as a Candidate of Monogenic Nephrotic Syndrome.

ABSTRACT:

Introduction

Most of the approximately 60 genes that if mutated cause steroid-resistant nephrotic syndrome (SRNS) are highly expressed in the glomerular podocyte, rendering SRNS a "podocytopathy."

Methods

We performed whole-exome sequencing (WES) in 1200 nephrotic syndrome (NS) patients.

Results

We discovered homozygous truncating and homozygous missense mutation in SYNPO2 (synaptopodin-2) (p.Lys1124? and p.Ala1134Thr) in 2 patients with childhood-onset NS. We found SYNPO2 expression in both podocytes and mesangial cells; however, notably, immunofluorescence staining of adult human and rat kidney cryosections indicated that SYNPO2 is localized mainly in mesangial cells. Subcellular localization studies reveal that in these cells SYNPO2 partially co-localizes with ?-actinin and filamin A-containing F-actin filaments. Upon transfection in mesangial cells or podocytes, EGFP-SYNPO2 co-localized with ?-actinin-4, which gene is mutated in autosomal dominant SRNS in humans. SYNPO2 overexpression increases mesangial cell migration rate (MMR), whereas shRNA knockdown reduces MMR. Decreased MMR was rescued by transfection of wild-type mouse Synpo2 cDNA but only partially by cDNA representing mutations from the NS patients. The increased mesangial cell migration rate (MMR) by SYNPO2 overexpression was inhibited by ARP complex inhibitor CK666. SYNPO2 shRNA knockdown in podocytes decreased active Rac1, which was rescued by transfection of wild-type SYNPO2 cDNA but not by cDNA representing any of the 2 mutant variants.

Conclusion

We show that SYNPO2 variants may lead to Rac1-ARP3 dysregulation, and may play a role in the pathogenesis of nephrotic syndrome.

SUBMITTER: Mao Y

PROVIDER: S-EPMC7879128 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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Recessive Mutations in <i>SYNPO2</i> as a Candidate of Monogenic Nephrotic Syndrome.

Mao Youying Y Schneider Ronen R van der Ven Peter F M PFM Assent Marvin M Lohanadan Keerthika K Klämbt Verena V Buerger Florian F Kitzler Thomas M TM Deutsch Konstantin K Nakayama Makiko M Majmundar Amar J AJ Mann Nina N Hermle Tobias T Onuchic-Whitford Ana C AC Zhou Wei W Margam Nandini Nagarajan NN Duncan Roy R Marquez Jonathan J Khokha Mustafa M Fathy Hanan M HM Kari Jameela A JA El Desoky Sherif S Eid Loai A LA Awad Hazem Subhi HS Al-Saffar Muna M Mane Shrikant S Lifton Richard P RP Fürst Dieter O DO Shril Shirlee S Hildebrandt Friedhelm F

Kidney international reports 20201110 2

<h4>Introduction</h4>Most of the approximately 60 genes that if mutated cause steroid-resistant nephrotic syndrome (SRNS) are highly expressed in the glomerular podocyte, rendering SRNS a "podocytopathy."<h4>Methods</h4>We performed whole-exome sequencing (WES) in 1200 nephrotic syndrome (NS) patients.<h4>Results</h4>We discovered homozygous truncating and homozygous missense mutation in <i>SYNPO2</i> (synaptopodin-2) (p.Lys1124∗ and p.Ala1134Thr) in 2 patients with childhood-onset NS. We found ...[more]

PMID: 33615072

Similar Datasets

Project description:BACKGROUND: Nephrotic syndrome is traditionally classified on the basis of the response to standard steroid treatment. Mutations in more than 24 genes have been associated with nephrotic syndrome in children, although the great majority of steroid-resistant cases have been attributed to mutations in three main genes: NPHS1, NPHS2 and WT1. The aims of this study were to identify mutations in these genes more frequently reported as mutated and to characterize each variation using different in silico prediction algorithms in order to understand their biological functions. METHODS: We performed direct sequence analysis of exons 8 and 9 of WT1, 8 exons of NPHS2 and 29 exons of NPHS1, including NPHS2 and NPHS1 intron-exon boundary sequences, as well as 700 bp of the 5' UTR from both genes in 27 steroid-resistant patients aged between 3 months and 18 years. RESULTS: Analysis of the NPHS2 gene revealed four missense mutations, one frameshift mutation and three variations in the 5' UTR. Four patients presented compound heterozygosis, and four other patients presented one heterozygous alteration only. WT1 and NPHS1 gene analysis did not reveal any mutations. DISCUSSION: This is the first study focusing on genetics of SRNS in Brazilian children. Identification of mutations is important because it could influence physicians' decision on patient treatment, as patients carrying mutations can be spared the side effects of immunosuppressive therapy and ultimately could be considered for kidney transplantation from a living donor. CONCLUSIONS: After molecular analysis of the genes more frequently reported as mutated in 27 steroid-resistant nephrotic syndrome patients, we identified NPHS2 mutations confirming the hereditary character of the kidney disease in only 14.8% of patients. Therefore, the next step is to perform a next generation sequencing based analysis of glomeluropathy-related panel of genes for the remaining patients in order to search for mutations in other genes related to steroid-resistant nephrotic syndrome.