Haploinsufficiency of the mouse Tshz3 gene leads to kidney dysfunction

Sanchez-Martin, I.; Magalhaes, P.; Fatmi, A.; Richard, F.; Vu Manh, T.-P.; Saurin, A. J.; Feuillet, G.; Denis, C.; Schanstra, J. P.; Zurbig, P.; Caubit, X.; Fasano, L.

doi:10.1101/2021.08.16.456481

bioRxiv · 10.1101/2021.08.16.456481

Haploinsufficiency of the mouse Tshz3 gene leads to kidney dysfunction

Sanchez-Martin, I.·Magalhaes, P.·Fatmi, A.·Richard, F.·Vu Manh, T.-P.·Saurin, A. J.·Feuillet, G.·Denis, C.·Schanstra, J. P.·Zurbig, P.·Caubit, X.·Fasano, L.

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Abstract

Renal tract defects and autism spectrum disorder (ASD) deficits represent the phenotypic core of the 19q12 deletion syndrome caused by the loss of one copy of the TSHZ3 gene. While a proportion of Tshz3 heterozygous (Tshz3+/lacZ) mice display ureteral defects, no kidney defects have been reported in these mice. The purpose of this study was to characterize the expression of Tshz3 in adult kidney as well as the renal physiological consequences of embryonic haploinsufficiency of Tshz3 by analyzing the morphology and function of Tshz3 heterozygous adult kidney. Here, we described Tshz3 expression in the smooth muscle and stromal cells lining the renal pelvis, the papilla and glomerular endothelial cells (GEnCs) of the adult kidney. Histological analysis showed that Tshz3+/lacZ adult kidney had an average of 29% fewer glomeruli than wild type kidney. Transmission electron microscopy (TEM) of Tshz3+/lacZ glomeruli revealed ultrastructural defects. Compared to wild type, Tshz3+/lacZ mice showed no difference in their urine parameters but lower blood urea, phosphates, magnesium and potassium at 2 months of age. At the molecular level, transcriptome analysis identified differentially expressed genes related to inflammatory processes in Tshz3+/lacZ compare to wild type (WT; control) adult kidneys. Lastly, analysis of the urinary peptidome revealed 33 peptides associated with Tshz3+/lacZ adult mice. These results provide the first evidence that in the mouse Tshz3 haploinsufficiency leads to cellular, molecular and functional abnormalities in the adult mouse kidney.

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Sanchez-Martin, I., Magalhaes, P., Fatmi, A., Richard, F., Vu Manh, T.-P., Saurin, A. J., Feuillet, G., Denis, C., Schanstra, J. P., Zurbig, P., Caubit, X., Fasano, L.. 2021-08-16. Haploinsufficiency of the mouse Tshz3 gene leads to kidney dysfunction. https://doi.org/10.1101/2021.08.16.456481

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