Neurogenic defects occur in LRIG2-associated urinary bladder disease

Celine Grenier, Filipa M. Lopes, Anna M. Cueto-González, Eulàlia Rovira-Moreno, Romy Gander, Benjamin W. Jarvis, Karen D. McCloskey, Alison M. Gurney, Glenda M. Beaman, William G. Newman, Adrian S. Woolf, Neil A. Roberts*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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Introduction: Urofacial, or Ochoa, syndrome (UFS) is an autosomal recessive disease featuring a dyssynergic bladder with detrusor smooth muscle contracting against an undilated outflow tract. It also features an abnormal grimace. Half of individuals with UFS carry biallelic variants in HPSE2, whereas other rare families carry variants in LRIG2. LRIG2 is immunodetected in pelvic ganglia sending autonomic axons into the bladder. Moreover, Lrig2 mutant mice have abnormal urination and abnormally patterned bladder nerves. We hypothesized that peripheral neurogenic defects underlie LRIG2-associated bladder dysfunction. 

Methods: We describe a new family with LRIG2-associated UFS and studied Lrig2 homozygous mutant mice with ex vivo physiological analyses. 

Results: The index case presented antenatally with urinary tract (UT) dilatation, and postnatally had urosepsis and functional bladder outlet obstruction. He had the grimace that, together with UT disease, characterizes UFS. Although HPSE2 sequencing was normal, he carried a homozygous, predicted pathogenic, LRIG2 stop variant (c.1939C>T; p.Arg647∗). Lrig2 mutant mice had enlarged bladders. Ex vivo physiology experiments showed neurogenic smooth muscle relaxation defects in the outflow tract, containing the urethra adjoining the bladder, and in detrusor contractility. Moreover, there were nuanced differences in physiological outflow tract defects between the sexes. 

Conclusion: Putting this family in the context of all reported UT disease-associated LRIG2 variants, the full UFS phenotype occurs with biallelic stop or frameshift variants, but missense variants lead to bladder-limited disease. Our murine observations support the hypothesis that UFS is a genetic autonomic neuropathy of the bladder affecting outflow tract and bladder body function.

Original languageEnglish
Pages (from-to)1417-1429
Number of pages13
JournalKidney International Reports
Issue number7
Publication statusPublished - 03 Jul 2023

Bibliographical note

Funding Information:
We acknowledge receiving research funding from the following: Medical Research Council (project grant MR/ L002744 /1 to ASW and WGN; project grant MR/ T016809 /1 to ASW, NAR, and FML; and Doctoral Training Programme to BWJ); Kidney Research United Kingdom (project grant Paed_RP/002/20190925 to WGN, GMB, and ASW; and Paed_RP/005/20190925 to NAR and ASW); Newlife Foundation (project grants 15-15/03 and 15-16/06 to WGN and ASW); the Manchester NIHR Biomedical Research Centre (IS-BRC-1215-20007 to WGN); and Kidneys for Life (start-up grant 2018 to NAR). We thank the European Reference Network on Rare Congenital Malformations and Rare Intellectual Disability ERN-ITHACA (EU Framework Partnership ID: 3HP-HP-FPA ERN-01-2016/739516) for their support. We thank the Manchester NIHR Biomedical Research Centre Rare Diseases theme, and the Manchester Rare Condition Centre for support.

Publisher Copyright:
© 2023 International Society of Nephrology


  • bladder
  • LRIG2
  • neurogenic
  • Ochoa
  • syndrome
  • urofacial

ASJC Scopus subject areas

  • Nephrology


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