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Kidney Week

Abstract: SA-PO621

In Vivo Mechanisms of LAMB2 Variants in Isolated Nephropathy: Insights from Knock-In Mouse Models

Session Information

Category: Genetic Diseases of the Kidneys

  • 1202 Genetic Diseases of the Kidneys: Non-Cystic

Authors

  • Okutsu, Mika, Tokyo Daigaku, Bunkyo-ku, Tokyo, Japan
  • Hashimoto, Taeko, Yamagata Daigaku, Yamagata, Yamagata, Japan
  • Kikkawa, Yamato, Tokyo Yakka Daigaku, Hachioji, Tokyo, Japan
  • Shimizu, Akira, Nihon Ika Daigaku, Bunkyo-ku, Tokyo, Japan
  • Harita, Yutaka, Tokyo Daigaku, Bunkyo-ku, Tokyo, Japan
Background

Loss of function mutations of LAMB2 encoding laminin β2 (β2) cause Pierson syndrome. Typical LAMB2 mutations found in Pierson syndrome are truncating mutations or mutations that inhibit extracellular secretion of β2. In recent years, a series of missense variants within specific domains of β2 (e.g. p.G699R) have been identified in cases of isolated nephropathy without extrarenal symptoms. The allele frequency of these mutations varies greatly regionally, with p.G699R being more frequent in East Asians (0.0085). We previously demonstrated that these variants have biochemical features distinct from loss-of function mutations causing Pierson syndrome. The variants found in isolated nephropathy preserved extracellular secretion of β2, but enhanced interactions between β2 and components in the glomerular basement membrane (GBM) (Kikkawa et al. JCI Insight 2021). To date, the in vivo effects of these variants are unknown.

Methods

We generated knock-in (KI) mice with the mutation corresponding to the LAMB2 p.G699R. We investigated the phenotype of KI mice, including the effects of adriamycin (ADR)-induced nephropathy.

Results

In the homozygous KI mice, β2 secretion in the GBM was maintained, which supports the results of the in vitro analysis. Long-term observation showed increased proteinuria in some homozygous KI mice. After ADR administration, KI mice had significantly more proteinuria than wild type mice. KI mice showed significantly increased mesangial area enlargement, focal thickening of the GBM and FSGS lesions in the renal tissue after ADR administration, and markedly enlarged subendothelial lumen and abnormal endothelial fenestrae by the electron microscopy. RNA-seq analysis suggests that KI mice have more intense changes in tissue inflammation than wild-type mice.

Conclusion

LAMB2 p.G699R exerts changes in the plasticity of glomerular injury by altering the adhesive capacity of the GBM, and could act as a risk factor for the development of renal disease.