Myogenic bladder defects in mouse models of human oculodentodigital dysplasia

To date, over 65 mutations in the gene encoding Cx43 have been linked to the autosomal dominant disease, oculodentodigital dysplasia (ODDD). A subset of these patients experience bladder incontinence which could be due to underlying neurogenic deterioration or aberrant myogenic regulation. Bladder smooth muscle cells (BSMCs) from wild-type and two Cx43 mutant lines (Cx43G60s and Cx43I130T) that mimic ODDD exhibit a significant reduction in total Cx43. Dye transfer studies revealed that the G60S mutant was a potent dominant-negative inhibitor of co-expressed Cx43, a property not equally shared by the I130T mutant. BSMCs from both mutant mouse strains were defective in their ability to contract indicative of phenotype changes due to harboring the Cx43 mutants. Upon stretching, Cx43 levels were significantly elevated in control and mutant containing BSMCs but the nonmuscle- myosin heavy chain A levels were only reduced in cells from control mice. While the Cx43G60s mutant mice showed no difference in voided urine volume or frequency, the Cx43I130T mice voided less frequently. Thus, like the diversity of morbidities seen in ODDD patients, genetically-modified mice also display mutation specific changes in bladder function. Furthermore, while mutant mice have compromised smooth muscle contraction and response to stretch, overriding bladder defects in Cx43I130T mice are likely complemented by neurogenic changes.

Source: BJ Cell - November 15, 2013 Category: Biochemistry Authors: T Huang, Q Shao, K Barr, J Simek, G I. Fishman, D W. Laird Tags: BJ Disease Source Type: research