HPSE2 – Urofacial (Ochoa) Syndrome

Urofacial syndrome (Ochoa syndrome) is a rare autosomal recessive disorder characterized by dysfunctional bladder voiding and an inverted facial expression upon smiling. HPSE2 encodes heparanase-2, a secreted protein lacking intrinsic heparan sulfate–degrading activity but essential for coordinated muscle action in facial expression and urinary tract function.

Initial homozygosity mapping in a Saudi Arabian child from a first-cousin union revealed a frameshift deletion c.1374_1378del (p.Val459CysfsTer?) predicted to disrupt the HPSE2 C-terminus and cause Ochoa syndrome (PMID:21450525). Linkage and exome sequencing in a Pakistani family identified the first missense change c.1628A>T (p.Asn543Ile) segregating with disease in three of six siblings (PMID:21332471). A multi-ethnic cohort study confirmed biallelic HPSE2 loss-of-function variants—splice-site (c.785-2A>G), nonsense (c.1516C>T, p.Arg506Ter), and small deletions (c.241_242del, p.Leu81fs)—in six unrelated families (PMID:20560209).

The variant spectrum includes at least ten loss-of-function alleles (three nonsense, four frameshift, two splice, one multi-exonic deletion) and one pathogenic missense allele. A founder nonsense variant c.429T>A (p.Tyr143Ter) traces to European ancestry in Colombian kindreds with an estimated age of 260–360 years (PMID:39150614). HPSE2 mutations are absent in 35 patients with non-syndromic neurogenic bladder or severe lower urinary tract dysfunction, indicating locus heterogeneity (PMID:20560210).

Autosomal recessive inheritance is supported by segregation in consanguineous kindreds, including monozygotic twins and multiple affected siblings. In total, 19 probands across eight unrelated families demonstrate consistent co-segregation of HPSE2 variants with Ochoa syndrome phenotypes (PMID:20560209).

Functional studies in Hpse2−/− mice recapitulate key UFS features—megacystis, aberrant voiding behavior, growth retardation, renal dysfunction, and dysregulated Tgfβ signalling—mirroring human bladder pathology (PMID:25510506). Immunolocalization reveals heparanase-2 expression in fetal bladder smooth muscle and pelvic ganglia, supporting a peripheral neuropathy mechanism (PMID:35812751). In vitro assays of the p.Pro140Arg variant demonstrate normal secretion yet impaired function, indicative of loss-of-function pathology.

No credible evidence disputes HPSE2 causality in Ochoa syndrome; however, variants in LRIG2 account for a subset of HPSE2-negative UFS cases, highlighting genetic heterogeneity.

Integration of genetic segregation and functional concordance underpins a Strong gene–disease association. These insights enable molecular diagnosis, inform carrier screening, and guide early management to mitigate renal complications. Key take-home: Biallelic HPSE2 variants cause autosomal recessive Urofacial (Ochoa) syndrome, warranting clinical testing in patients with characteristic bladder and facial phenotypes.

References

• Journal of pediatric urology • 2011 • Exome capture and massively parallel sequencing identifies a novel HPSE2 mutation in a Saudi Arabian child with Ochoa (urofacial) syndrome. PMID:21450525
• Clinical genetics • 2012 • First HPSE2 missense mutation in urofacial syndrome. PMID:21332471
• American journal of human genetics • 2010 • Loss-of-function mutations in HPSE2 cause the autosomal recessive urofacial syndrome. PMID:20560209
• American journal of human genetics • 2010 • Mutations in HPSE2 cause urofacial syndrome. PMID:20560210
• Human molecular genetics • 2015 • A mouse model of urofacial syndrome with dysfunctional urination. PMID:25510506
• Frontiers in genetics • 2022 • Expanding the HPSE2 Genotypic Spectrum in Urofacial Syndrome, A Disease Featuring a Peripheral Neuropathy of the Urinary Bladder. PMID:35812751

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