Abstract
Urofacial syndrome (UFS) is an autosomal recessive disease characterized 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 hypothesized that bladder neurophysiology is abnormal Hpse2 mutant mice. Myography was used to study bladder bodies and outflow tracts isolated from juvenile mice. Myogenic function was analyzed 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 blot analysis. Nitrergic nerve-mediated relaxation of precontracted mutant outflow tracts was significantly decreased vs littermate controls. The contractile ability of mutant outflow tracts was normal as assessed by KCl and the α1-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. The Hpse2 model of UFS features aberrant bladder neuromuscular physiology. Further work is required to determine whether similar aberrations occur in patients with UFS.
Highlights
| INTRODUCTIONThese is urofacial, or Ochoa, syndrome (UFS), a rare but potentially devastating autosomal recessive disorder.[2,3,4]
Following on from the above observations that Hpse[2] mutant mice have both urination defects and disordered bladder nerves, we hypothesized that bladder neurophysiology would be perturbed in this animal model
Our results show that in Hpse[2] mutants, functional neurophysiological defects are present in the bladder body and outflow
Summary
These is urofacial, or Ochoa, syndrome (UFS), a rare but potentially devastating autosomal recessive disorder.[2,3,4]. Heparanase 2 and LRIG2 have been immunodetected in nerves located between smooth muscle bundles in the human fetal bladder[9] and in mouse pelvic ganglia,[8] structures sending postganglionic autonomic motor neurons to the bladder.[11] Mice with biallelic Hpse[2] or Lrig[2] mutations have abnormal patterns of peripherin expressing bladder nerves[12]; an overabundance was detected in the bladder body, while fewer nitric oxide synthase (nNOS) expressing nerves spanning pelvic ganglia flanking the outflow tract.[12] In healthy mice, nitrergic neurons dilate the outflow tract.[13,14] both Hpse[2] and Lrig[2] mutant mouse bladders are depleted of Nos[1], the transcript encoding nNOS,[12] and both Hpse[2] and Lrig[2] mutant mouse models have urination defects similar to people with UFS.[12]. Following on from the above observations that Hpse[2] mutant mice have both urination defects and disordered bladder nerves, we hypothesized that bladder neurophysiology would be perturbed in this animal model. We used myography to characterize bladder outflow and bladder body neurophysiology in Hpse[2] mutant mice. Further work is required to determine whether similar aberrations occur in individuals affected by UFS
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