Neurogenic Defects Occur in LRIG2-Associated Urinary Bladder Disease

Area of Science:

• Genetics
• Urology
• Neuroscience

Background:

• Urofacial (UFS) syndrome is an autosomal recessive disorder characterized by a dyssynergic bladder and abnormal facial grimace.
• Biallelic variants in HPSE2 cause UFS in half of affected individuals, while LRIG2 variants are found in other rare families.

Purpose of the Study:

• To investigate the role of LRIG2 in UFS and associated bladder dysfunction.
• To explore the underlying peripheral neurogenic defects in LRIG2-associated UFS.

Main Methods:

• Described a new family with LRIG2-associated UFS.
• Studied Lrig2 homozygous mutant mice using ex vivo physiological analyses.

Main Results:

• Identified a homozygous pathogenic LRIG2 stop variant in the index case with UFS.
• Lrig2 mutant mice exhibited enlarged bladders and neurogenic smooth muscle relaxation defects in the bladder outflow tract and detrusor.
• Observed sex-specific differences in physiological outflow tract defects in mutant mice.

Conclusions:

• LRIG2 variants, particularly stop or frameshift types, cause the full UFS phenotype, while missense variants result in bladder-limited disease.
• Supports the hypothesis that UFS is a genetic autonomic neuropathy of the bladder, impacting outflow tract and bladder body function.