LRIG2 – Ochoa syndrome

LRIG2 has been implicated in the pathogenesis of Ochoa syndrome, a rare autosomal recessive disorder characterized by a dyssynergic urinary bladder and an abnormal facial grimace. Several independent studies have documented biallelic variants in LRIG2 that co‐segregate with the full clinical features of the syndrome, including both bladder dysfunction and associated renal complications (PMID:37441484, PMID:23313374). These reports include a new family in which the index case presented with antenatal urinary tract dilatation, urosepsis, and a characteristic grimace, despite normal HPSE2 sequencing. Such findings underscore the clinical relevance of LRIG2 in the neurogenic underpinnings of urinary bladder dysfunction.

Genetic evidence from multipatient studies further expands the variant spectrum linked to Ochoa syndrome. At least five unrelated families have been documented to carry biallelic loss‐of‐function variants, with some cases exhibiting stop or frameshift mutations and others showing missense variants associated with a milder, bladder‐limited phenotype (PMID:23313374). One representative variant, c.1939C>T (p.Arg647Ter), results in a truncated protein consistent with loss of function and appears recurrent among patients with the full UFS phenotype. These combined case reports and series provide robust genetic support for the LRIG2–Ochoa syndrome association.

Functional studies have bolstered the genetic findings by demonstrating a clear neurogenic mechanism. Lrig2 mutant mice exhibit key features of the human disease including aberrant nerve patterning in the urinary bladder and defects in smooth muscle contractility, which recapitulate the clinical phenotype of functional bladder outlet obstruction. In-depth physiological analyses in animal models have highlighted altered neurogenic regulation of both the bladder body and the outflow tract, adding biological plausibility to the observed human phenotype (PMID:37441484, PMID:30885509).

The convergence of genetic and experimental evidence, including segregation in multiple families and functional models reproducing core aspects of the syndrome, supports a strong association between LRIG2 and Ochoa syndrome. Although additional genetic factors (such as variants in HPSE2) contribute to the disease spectrum, the evidence for LRIG2 is compelling and consistent across diverse study designs. This integrated approach reinforces the critical role of LRIG2 in the proper development and function of the autonomic nervous system in the lower urinary tract.

In summary, the current body of evidence qualifies the LRIG2–Ochoa syndrome association as strong. Clinicians and researchers can rely on genetic testing for LRIG2 variants, such as c.1939C>T (p.Arg647Ter), as an important diagnostic tool that complements functional studies and informs precision medicine. Recognizing the spectrum of phenotypes related to different classes of LRIG2 variants further enhances diagnostic decision‑making and facilitates targeted therapeutic strategies.

Key Take‑Home: The robust genetic and functional evidence supporting LRIG2’s role in Ochoa syndrome strongly underscores its clinical utility in the diagnostic evaluation of patients with neurogenic bladder dysfunction and related renal complications.

References

• Kidney international reports • 2023 • Neurogenic Defects Occur in LRIG2-Associated Urinary Bladder Disease PMID:37441484
• American journal of human genetics • 2013 • LRIG2 mutations cause urofacial syndrome PMID:23313374
• Kidney international • 2019 • Lrig2 and Hpse2, mutated in urofacial syndrome, pattern nerves in the urinary bladder PMID:30885509
• Frontiers in genetics • 2022 • Expanding the HPSE2 Genotypic Spectrum in Urofacial Syndrome PMID:35812751

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