Myogenic bladder defects in mouse models of human oculodentodigital dysplasia.
To date, over 65 mutations in the gene encoding Cx43 (connexin43) have been linked to the autosomal-dominant disease ODDD (oculodentodigital dysplasia). A subset of these patients experience bladder incontinence which could be due to underlying neurogenic deterioration or aberrant myogenic regulation. BSMCs (bladder smooth muscle cells) from wild-type and two Cx43 mutant lines (Cx43(G60S) and Cx43(I130T)) 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, which is indicative of phenotype changes due to harbouring the Cx43 mutants. Upon stretching, Cx43 levels were significantly elevated in controls and mutants containing BSMCs, but the non-muscle myosin heavy chain A levels were only reduced in cells from control mice. Although the Cx43(G60S) mutant mice showed no difference in voided urine volume or frequency, the Cx43(I130T) mice voided less frequently. Thus, similar to the diversity of morbidities seen in ODDD patients, genetically modified mice also display mutation-specific changes in bladder function. Furthermore, although mutant mice have compromised smooth muscle contraction and response to stretch, overriding bladder defects in Cx43(I130T) mice are likely to be complemented by neurogenic changes.
*Department of Anatomy and Cell Biology, University of Western Ontario, London, Ontario, Canada, N6A 5C1.
Tao
T
Huang
*Department of Anatomy and Cell Biology, University of Western Ontario, London, Ontario, Canada, N6A 5C1.
Qing
Q
Shao
*Department of Anatomy and Cell Biology, University of Western Ontario, London, Ontario, Canada, N6A 5C1.
Kevin
K
Barr
†Department of Physiology and Pharmacology, University of Western Ontario, London, Ontario, Canada, N6A 5C1.
Jamie
J
Simek
‡Division of Cardiology, New York University School of Medicine, New York, NY 10016, U.S.A.
Glenn I
GI
Fishman
Dale W
DW
Laird
D019943:Amino Acid Substitution; D000818:Animals; D002450:Cell Communication; D002478:Cells, Cultured; D018031:Connexin 43 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D019465:Craniofacial Abnormalities / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D004195:Disease Models, Animal; D005124:Eye Abnormalities / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D005532:Foot Deformities, Congenital / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D017629:Gap Junctions / Q000378:metabolism; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D009119:Muscle Contraction; D009130:Muscle, Smooth / Q000737:chemistry / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D009135:Muscular Diseases / Q000209:etiology* / Q000503:physiopathology; D050505:Mutant Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D018995:Myosin Heavy Chains / Q000378:metabolism; D013576:Syndactyly / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D014071:Tooth Abnormalities / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D001743:Urinary Bladder / Q000737:chemistry / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D001750:Urinary Bladder, Neurogenic / Q000209:etiology* / Q000503:physiopathology; D014549:Urinary Incontinence / Q000209:etiology
D018031:Connexin 43; C543076:GJA1 protein, mouse; D050505:Mutant Proteins; C471698:connexin 43alpha1, mouse; D018995:Myosin Heavy Chains