INVS – Nephronophthisis 2

INVS is associated with autosomal recessive Nephronophthisis 2, characterized by juvenile end-stage renal disease, tubular basement membrane disruption and occasional situs inversus totalis (HP:0001696). Biallelic loss-of-function variants have been reported in three probands from two families: homozygous c.2695C>T (p.Arg899Ter)(PMID:20798123) in siblings with discordant situs inversus and juvenile ESRD, and compound heterozygous c.1789C>T (p.Arg597Ter) plus c.796+5G>A (PMID:31706999) in an infantile case with polycystic kidneys. Histopathology shows chronic interstitial nephritis with corticomedullary cysts and up-regulated canonical Wnt/β-catenin signaling in patient tubules(PMID:20798123). Functional studies demonstrate that inversin binds RNA and is recruited to TIA-1–positive stress granules alongside BICC1 upon translational inhibition(PMID:32994509), and that inversin deficiency perturbs cortical actin remodeling and mitotic rounding in cell and mouse models, leading to spindle mispositioning and altered nephron morphogenesis(PMID:23515530). Collectively, these data support a loss-of-function mechanism for INVS in nephronophthisis 2. Key Take-home: Biallelic truncating and splice site variants in INVS underlie juvenile nephronophthisis with variable situs inversus via dysregulated Wnt signaling and cytoskeletal defects.

References

• Nephrology, dialysis, transplantation • 2010 • A homozygous mutation in INVS causing juvenile nephronophthisis with abnormal reactivity of the Wnt/beta-catenin pathway. PMID:20798123
• Gene • 2020 • Novel splice site and nonsense variants in INVS cause infantile nephronophthisis. PMID:31706999
• Scientific Reports • 2020 • Nephronophthisis gene products display RNA-binding properties and are recruited to stress granules. PMID:32994509
• American Journal of Physiology. Cell Physiology • 2013 • Inversin modulates the cortical actin network during mitosis. PMID:23515530

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