Prenatal Diagnosis and Molecular Cytogenetic Characterization of Xp22.32p22.31 microduplication in a Chinese family

Objectives: To explore the relationship between Xp22.32p22.31 microduplication and mental retardation identifiable by chromosomal G-banding and chromosomal microarray analysis (CMA). Material and methods: Chromosomal G-banding, CMA, and physical and mental examinations were performed on four members of a Chinese family. Results: The mother and one baby had the same microduplication (arr[GRCh37] Xp22.32p22.31(5970505-6075215)x2), and the baby had mental retardation. Conclusions: Xp22.32p22.31 microduplication in males could cause mental retardation. Combination of NIPT, prenatal ultrasound, chromosomal G-banding and CMA has high accuracy in risk assessment for prenatal diagnosis

Blockade of myeloid differentiation 2 attenuates diabetic nephropathy by reducing activation of the renin-angiotensin system in mouse kidneys

Background and Purpose: Both innate immunity and the renin-angiotensin system (RAS) play important roles in the pathogenesis of diabetic nephropathy (DN). Myeloid differentiation factor 2 (MD2) is a co-receptor of toll-like receptor 4 (TLR4) in innate immunity. While TLR4 is involved in the development of DN, the role of MD2 in DN has not been characterized. It also remains unclear whether the MD2/TLR4 signalling pathway is associated with RAS activation in diabetes. Experimental Approach: MD2 was blocked using siRNA or the low MW inhibitor, L6H9, in renal proximal tubular cells (NRK-52E cells) exposed to high concentrations of glucose (HG). In vivo, C57BL/6 and MD2−/− mice were injected with streptozotocin to induce Type 1 diabetes and nephropathy. Key Results: Inhibition of MD2 by genetic knockdown or the inhibitor L6H9 suppressed HG-induced expression of ACE and angiotensin receptors and production of angiotensin II in NRK-52E cells, along with decreased fibrosis markers (TGF-β and collagen IV). Inhibition of the MD2/TLR4-MAPKs pathway did not affect HG-induced renin overproduction. In vivo, using the streptozotocin-induced diabetic mice, MD2 was overexpressed in diabetic kidney. MD2 gene knockout or L6H9 attenuated renal fibrosis and dysfunction by suppressing local RAS activation and inflammation. Conclusions and Implications: Hyperglycaemia activated the MD2/TLR4-MAPKs signalling cascade to induce renal RAS activation, leading to renal fibrosis and dysfunction. Pharmacological inhibition of MD2 may be considered as a therapeutic approach to mitigate DN and the low MW inhibitor L6H9 could be a candidate for such therapy