Lrig2 and Hpse2, mutated in urofacial syndrome, pattern nerves in the urinary bladder

Abstract

Mutations in leucine-rich-repeats and immunoglobulin-like-domains 2 (LRIG2) or in heparanase 2 (HPSE2) cause urofacial syndrome, a devastating autosomal recessive disease of functional bladder outlet obstruction. It has been speculated that urofacial syndrome has a neural basis, but it is unknown whether defects in urinary bladder innervation are present. We hypothesized that urofacial syndrome features a peripheral neuropathy of the bladder. Mice with homozygous targeted Lrig2 mutations had urinary defects resembling those found in urofacial syndrome. There was no anatomical blockage of the outflow tract, consistent with a functional bladder outlet obstruction. Transcriptome analysis revealed differential expression of 12 known transcripts in addition to Lrig2 , including 8 with established roles in neurobiology. Mice with homozygous mutations in either Lrig2 or Hpse2 had increased nerve density within the body of the urinary bladder and decreased nerve density around the urinary outflow tract. In a sample of 155 children with chronic kidney disease and urinary symptoms, we discovered novel homozygous missense LRIG2 variants that were predicted to be pathogenic in 2 individuals with non-syndromic bladder outlet obstruction. These observations provide evidence that a peripheral neuropathy is central to the pathobiology of functional bladder outlet obstruction in urofacial syndrome, and emphasize the importance of LRIG2 and heparanase 2 for nerve patterning in the urinary tract.

Dysfunctional bladder neurophysiology in urofacial syndrome Hpse2 mutant mice

“…This could be investigated further by comparing the effects of direct activators of the NO‐cGMP signaling pathway on mutant and control mice. Consistent with the loss of EFS‐induced relaxation, however, Hpse2 mutant mice have fewer nerves in their outflow tracts and reduced Nos1 transcripts 12 . Therefore fewer nitrergic nerves may be the simplest explanation for impaired outflow relaxation upon nerve stimulation.…”

“…It has been reported that there is an overabundance of nerves in the bladder body of the Hpse2 mutant mouse 12 . Moreover, in children with UFS, the bladder has been described as hypercontractile 2 .…”

“…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 Hpse2 or Lrig2 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 .…”

A homozygous missense variant in CHRM3 associated with familial urinary bladder disease

“…In other cases, genes that have been associated with bladder malformations code for proteins implicated in the neuro‐muscular circuits required for bladder voiding . As examples, HPSE2 codes for heparanase 2 and LRIG2 codes for leucine rich repeats and immunoglobulin‐like domains 2, proteins detected in foetal bladder nerves; variants of these genes are implicated in urofacial syndrome …”

“…12,13 As examples, HPSE2 codes for heparanase 2 and LRIG2 codes for leucine rich repeats and immunoglobulin-like domains 2, proteins detected in foetal bladder nerves; variants of these genes are implicated in urofacial syndrome. 5,6,14 Also in the neuro-muscular category is CHRM3 that encodes M3, the key acetylcholine receptor expressed by detrusor smooth muscle cells that is required for parasympathetic-driven detrusor contraction and bladder emptying. 2,13,15 Weber et al 1 reported a family with six brothers who were born to consanguineous Turkish parents.…”