Dysfunctional bladder neurophysiology in urofacial syndrome Hpse2 mutant mice

Aims. Urofacial syndrome (UFS) is an autosomal recessive disease characterised by detrusor contraction against an incompletely dilated outflow tract. This dyssynergia causes dribbling incontinence and incomplete voiding. Around half of individuals with UFS have biallelic mutations of HPSE2 that encodes heparanase 2, a protein found in pelvic ganglia and bladder nerves. Homozygous Hpse2 mutant mice have abnormal patterns of nerves in the bladder body and outflow tract, and also have dysfunctional urinary voiding. We therefore characterised bladder neurophysiology in Hpse2 mutant mice.

Methods. Myography was used to study bladder bodies and outflow tracts isolated from juvenile mice. Myogenic function was analysed after chemical stimulation or blockade of key receptors. Neurogenic function was assessed by electrical field stimulation (EFS). Muscarinic receptor expression was semi-quantified by western blotting.

Results. Nitrergic nerve-mediated relaxation of pre-contracted mutant outflow tracts was significantly decreased versus littermate controls. The contractile ability of mutant outflow tracts was normal as assessed by KCl and the 1-adrenoceptor agonist phenylephrine. EFS of mutant bladder bodies induced significantly weaker contractions than controls. Conversely, the muscarinic agonist carbachol induced significantly stronger contractions of bladder body than controls.

Conclusions. The Hpse2 model of UFS features aberrant bladder neuro-muscular physiology, which may explain dyssynergia symptoms in patients.