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Urinary tract effects of HPSE2 mutations.

ABSTRACT: Urofacial syndrome (UFS) is an autosomal recessive congenital disease featuring grimacing and incomplete bladder emptying. Mutations of HPSE2, encoding heparanase 2, a heparanase 1 inhibitor, occur in UFS, but knowledge about the HPSE2 mutation spectrum is limited. Here, seven UFS kindreds with HPSE2 mutations are presented, including one with deleted asparagine 254, suggesting a role for this amino acid, which is conserved in vertebrate orthologs. HPSE2 mutations were absent in 23 non-neurogenic neurogenic bladder probands and, of 439 families with nonsyndromic vesicoureteric reflux, only one carried a putative pathogenic HPSE2 variant. Homozygous Hpse2 mutant mouse bladders contained urine more often than did wild-type organs, phenocopying human UFS. Pelvic ganglia neural cell bodies contained heparanase 1, heparanase 2, and leucine-rich repeats and immunoglobulin-like domains-2 (LRIG2), which is mutated in certain UFS families. In conclusion, heparanase 2 is an autonomic neural protein implicated in bladder emptying, but HPSE2 variants are uncommon in urinary diseases resembling UFS.

SUBMITTER: Stuart HM

PROVIDER: S-EPMC4378092 | biostudies-literature | 2015 Apr

REPOSITORIES: biostudies-literature

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Urinary tract effects of HPSE2 mutations.

Stuart Helen M HM Roberts Neil A NA Hilton Emma N EN McKenzie Edward A EA Daly Sarah B SB Hadfield Kristen D KD Rahal Jeffery S JS Gardiner Natalie J NJ Tanley Simon W SW Lewis Malcolm A MA Sites Emily E Angle Brad B Alves Cláudia C Lourenço Teresa T Rodrigues Márcia M Calado Angelina A Amado Marta M Guerreiro Nancy N Serras Inês I Beetz Christian C Varga Rita-Eva RE Silay Mesrur Selcuk MS Darlow John M JM Dobson Mark G MG Barton David E DE Hunziker Manuela M Puri Prem P Feather Sally A SA Goodship Judith A JA Goodship Timothy H J TH Lambert Heather J HJ Cordell Heather J HJ Saggar Anand A Kinali Maria M Lorenz Christian C Moeller Kristina K Schaefer Franz F Bayazit Aysun K AK Weber Stefanie S Newman William G WG Woolf Adrian S AS

Journal of the American Society of Nephrology : JASN 20140821 4

Urofacial syndrome (UFS) is an autosomal recessive congenital disease featuring grimacing and incomplete bladder emptying. Mutations of HPSE2, encoding heparanase 2, a heparanase 1 inhibitor, occur in UFS, but knowledge about the HPSE2 mutation spectrum is limited. Here, seven UFS kindreds with HPSE2 mutations are presented, including one with deleted asparagine 254, suggesting a role for this amino acid, which is conserved in vertebrate orthologs. HPSE2 mutations were absent in 23 non-neurogeni ...[more]

PMID: 25145936

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Project description:BackgroundCongenital abnormalities of the kidney and the urinary tract are the most common cause of pediatric kidney failure. These disorders are highly heterogeneous, and the etiologic factors are poorly understood.MethodsWe performed genomewide linkage analysis and whole-exome sequencing in a family with an autosomal dominant form of congenital abnormalities of the kidney or urinary tract (seven affected family members). We also performed a sequence analysis in 311 unrelated patients, as well as histologic and functional studies.ResultsLinkage analysis identified five regions of the genome that were shared among all affected family members. Exome sequencing identified a single, rare, deleterious variant within these linkage intervals, a heterozygous splice-site mutation in the dual serine-threonine and tyrosine protein kinase gene (DSTYK). This variant, which resulted in aberrant splicing of messenger RNA, was present in all affected family members. Additional, independent DSTYK mutations, including nonsense and splice-site mutations, were detected in 7 of 311 unrelated patients. DSTYK is highly expressed in the maturing epithelia of all major organs, localizing to cell membranes. Knockdown in zebrafish resulted in developmental defects in multiple organs, which suggested loss of fibroblast growth factor (FGF) signaling. Consistent with this finding is the observation that DSTYK colocalizes with FGF receptors in the ureteric bud and metanephric mesenchyme. DSTYK knockdown in human embryonic kidney cells inhibited FGF-stimulated phosphorylation of extracellular-signal-regulated kinase (ERK), the principal signal downstream of receptor tyrosine kinases.ConclusionsWe detected independent DSTYK mutations in 2.3% of patients with congenital abnormalities of the kidney or urinary tract, a finding that suggests that DSTYK is a major determinant of human urinary tract development, downstream of FGF signaling. (Funded by the National Institutes of Health and others.).

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Urinary tract effects of HPSE2 mutations.

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Urinary tract effects of HPSE2 mutations.

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