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The Wnts can be considered as candidates for the Congenital Anomaly of Kidney and Urinary Tract, CAKUT diseases since they take part in the control of kidney organogenesis. Of them Wnt5a is expressed in ureteric bud (UB) and its deficiency leads to duplex collecting system (13/90) uni- or bilateral kidney agenesis (10/90), hypoplasia with altered pattern of ureteric tree organization (42/90) and lobularization defects with partly fused ureter trunks (25/90) unlike in controls. The UB had also notably less tips due to Wnt5a deficiency being at E15.5 306 and at E16.5 765 corresponding to 428 and 1022 in control (p<0.02; p<0.03) respectively. These changes due to Wnt5a knock out associated with anomalies in the ultrastructure of the UB daughter epithelial cells. The basement membrane (BM) was malformed so that the BM thickness increased from 46.3 nm to 71.2 nm (p<0.01) at E16.5 in the Wnt5a knock out when compared to control. Expression of a panel of BM components such as laminin and of type IV collagen was also reduced due to the Wnt5a knock out. The P4ha1 gene that encodes a catalytic subunit of collagen prolyl 4-hydroxylase I (C-P4H-I) in collagen synthesis expression and the overall C-P4H enzyme activity were elevated by around 26% due to impairment in Wnt5a function from control. The compound Wnt5a+/-;P4ha1+/- embryos demonstrated Wnt5a-/- related defects, for example local hyperplasia in the UB tree. A R260H WNT5A variant was identified from renal human disease cohort. Functional studies of the consequence of the corresponding mouse variant in comparison to normal ligand reduced Wnt5a-signalling in vitro. Together Wnt5a has a novel function in kidney organogenesis by contributing to patterning of UB derived collecting duct development contributing putatively to congenital disease. [ABSTRACT FROM AUTHOR]

Study Type - Aetiology (individual cohort) Level of Evidence 2b What's known on the subject? and What does the study add? Recent studies have already shown associations between generalized joint hypermobility (GJH) and voiding and defecation dysfunction and/or slow transit constipation. Changes in extracellular matrix composition in vesico-ureteric junction of vesico-ureteral reflux (VUR) patients were also observed previously. This study is the first to assess joint mobility as a parameter for connective tissue composition in vesico-ureteral reflux. We convincingly demonstrate that VUR patients have significantly more hypermobile joints compared to controls and this provides a new angle to the intriguing subjects of development of VUR and susceptibility to VUR. OBJECTIVE [ABSTRACT FROM AUTHOR]

Integrins are transmembrane aß glycoproteins that connect the extracellular matrix to the cytoskeleton. The laminin-binding integrin a3ß1 is expressed at high levels in lung epithelium and in kidney podocytes. In podocytes, a3ß1 associates with the tetraspanin CD151 to maintain a functional filtration barrier. Here, we report on a patient homozygous for a novel missense mutation in the human ITGA3 gene, causing fatal interstitial lung disease and congenital nephrotic syndrome. The mutation caused an alanine-to-serine substitution in the integrin a3 subunit, thereby introducing an N-glycosylation motif at amino acid position 349. We expressed this mutant form of ITGA3 in murine podocytes and found that hyperglycosylation of the a3 precursor prevented its heterodimerization with ß1, whereas CD151 association with the a3 subunit occurred normally. Consequently, the ß1 precursor accumulated in the ER, and the mutant a3 precursor was degraded by the ubiquitin-proteasome system. Thus, these findings uncover a gain-of-glycosylation mutation in ITGA3 that prevents the biosynthesis of functional a3ß1, causing a fatal multiorgan disorder. [ABSTRACT FROM AUTHOR]