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Hum Mol Genet 2014 Aug 15;2316:4302-14. doi: 10.1093/hmg/ddu147.
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Heparanase 2, mutated in urofacial syndrome, mediates peripheral neural development in Xenopus.

Roberts NA , Woolf AS , Stuart HM , Thuret R , McKenzie EA , Newman WG , Hilton EN .

Urofacial syndrome (UFS; previously Ochoa syndrome) is an autosomal recessive disease characterized by incomplete bladder emptying during micturition. This is associated with a dyssynergia in which the urethral walls contract at the same time as the detrusor smooth muscle in the body of the bladder. UFS is also characterized by an abnormal facial expression upon smiling, and bilateral weakness in the distribution of the facial nerve has been reported. Biallelic mutations in HPSE2 occur in UFS. This gene encodes heparanase 2, a protein which inhibits the activity of heparanase. Here, we demonstrate, for the first time, an in vivo developmental role for heparanase 2. We identified the Xenopus orthologue of heparanase 2 and showed that the protein is localized to the embryonic ventrolateral neural tube where motor neurons arise. Morpholino-induced loss of heparanase 2 caused embryonic skeletal muscle paralysis, and morphant motor neurons had aberrant morphology including less linear paths and less compactly-bundled axons than normal. Biochemical analyses demonstrated that loss of heparanase 2 led to upregulation of fibroblast growth factor 2/phosphorylated extracellular signal-related kinase signalling and to alterations in levels of transcripts encoding neural- and muscle-associated molecules. Thus, a key role of heparanase 2 is to buffer growth factor signalling in motor neuron development. These results shed light on the pathogenic mechanisms underpinning the clinical features of UFS and support the contention that congenital peripheral neuropathy is a key feature of this disorder.

PubMed ID: 24691552
PMC ID: PMC4103677
Article link: Hum Mol Genet
Grant support: [+]

Species referenced: Xenopus
Genes referenced: chrnb2 drosha fgf2 fgfr1 fgfr2 got1 hpse hpse2 loxl4 lrig2 myh11 myod1 olig2 slc25a28 syn1 tuba8
GO keywords: swimming behavior [+]
Antibodies: hpse2 Ab1
Morpholinos: hpse2 MO1

Disease Ontology terms: urofacial syndrome
Phenotypes: Xtr Wt + hpse2 MO (fig.4.e) [+]

Article Images: [+] show captions
References [+] :
Al Badr, Exome capture and massively parallel sequencing identifies a novel HPSE2 mutation in a Saudi Arabian child with Ochoa (urofacial) syndrome. 2011, Pubmed