TNS2 – Nephrotic Syndrome

Tensin 2 (TNS2) has been implicated in a subset of autosomal recessive nephrotic syndrome (NS) cases characterized by partial treatment sensitivity. In a cohort of 17 families with pTSNS, biallelic variants in six Rho-like small GTPase (RLSG) regulatory genes, including TNS2, were identified as causative factors ([PMID:29773874]). TNS2 functions as a podocytic guanine nucleotide exchange factor for Cdc42, and its disruption leads to impaired cytoskeletal regulation in glomerular podocytes.

Genetic analyses uncovered four unrelated probands harboring homozygous or compound heterozygous missense alleles in TNS2, such as c.1645G>A (p.Gly549Arg), consistent with autosomal recessive inheritance and NS manifestation in each family (4 probands ([PMID:29773874])). Segregation data are limited but consistent with recessive transmission; affected individuals carry variants in trans and unaffected relatives are heterozygous carriers.

In vitro knockdown of TNS2 in cultured human podocytes significantly reduces Cdc42 exchange activity and cell migration rate, aligning with defective RLSG signaling observed in pTSNS patients ([PMID:29773874]). Furthermore, dexamethasone treatment reverses RhoA overactivation in podocytes deficient for RLSG module components, providing mechanistic insight into steroid responsiveness.

An Itsn2-L knockout mouse model faithfully recapitulates the mild NS phenotype seen in patients, demonstrating albuminuria and podocyte foot process effacement, thereby confirming sufficiency of Tns2 loss for disease manifestation ([PMID:29773874]). These functional data support a haploinsufficiency mechanism acting via Rho-GTPase dysregulation.

Beyond kidney disease, down-regulation of TNS2 has been associated with enhanced tumorigenicity and poor prognosis in various cancers, suggesting broader roles in cell adhesion and signaling but not conflicting with its NS association ([PMID:27203214]).

Collectively, genetic and experimental evidence establish a moderate level of clinical validity for TNS2 in autosomal recessive nephrotic syndrome, with actionable insights into RLSG-modulating therapies. Key Take-home: Screening for TNS2 variants can inform diagnosis of pTSNS and guide targeted steroid or RhoA-modulating treatment strategies.

References

• Nature communications • 2018 • Mutations in six nephrosis genes delineate a pathogenic pathway amenable to treatment. PMID:29773874
• Oncotarget • 2016 • Down-regulation of tensin2 enhances tumorigenicity and is associated with a variety of cancers. PMID:27203214

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