First HPSE2 missense mutation in urofacial syndrome

Abstract

Urofacial syndrome (UFS) describes the combination of urological problems and an inverted facial expression upon attempts to smile. Seventeen independent familial cases from different ethnicities have been described so far. Some of these have been linked to chromosome 10q. Very recently, homozygous loss-of-function mutations affecting the gene HPSE2 were identified in nine cases. Here, we describe a consanguineous UFS family from Pakistan with three of six siblings affected. We establish linkage to the chromosome 10q critical region and identify two non-synonymous HPSE2 variants. In silico analysis and screening of controls defines c.631T>C (p.Y211H) as a novel benign SNP and c.1628A>T (p.N543I) as the disease-causing mutation. Our study exemplifies the challenges in proper clinical diagnosis of UFS and, thereby, supports the hypothesis of the disease being under diagnosed. By identifying the first HPSE2 missense mutation it also provides a starting point for studies aimed at functionally understanding the unusual combination of symptoms as characterizing UFS.

Urinary Tract Effects of HPSE2 Mutations

“…The Supplemental Material details their clinical histories and investigations, and Supplemental Figure 1 illustrates examples of facial grimacing and dysmorphic bladders. Considering these and previously published mutations [4][5][6][7] ( Figure 1A), it is clear that pathogenic HPSE2 mutations are found across the gene's coding region. Most (i.e., nonsense or frameshift mutations) would cause loss of function, but a subset may generate abnormal proteins.…”

“…[1][2][3][4][5][6][7] Affected children have enuresis and incomplete bladder emptying associated with detrusor and bladder outlet dyssynergic contractions. ESRD, urosepsis and vesicoureteric reflux (VUR) can occur.…”

“…Biallelic mutations of HPSE2 cause UFS. [4][5][6][7] HPSE2 encodes heparanase 2, 8 which inhibits endo-b-Dglucuronidase activity of heparanase 1, 9 itself implicated in releasing growth factors from heparan sulfate proteoglycans. [10][11][12] Since the first descriptions of HPSE2 mutations in UFS in 2010, 4,5 only two further such families have been reported.…”

“…[10][11][12] Since the first descriptions of HPSE2 mutations in UFS in 2010, 4,5 only two further such families have been reported. 6,7 We here describe seven new UFS kindreds with HPSE2 mutations, representing the largest series to date of genetically defined, overtly unrelated families. Their mutations and key clinical features are listed in Table 1.…”

“…12 It is predicted to be nitrogen-linked glycosylated 13 (Figure 1A) and may direct endoplasmic reticulum processing of heparanase 2. 13 Mahmood et al 7 reported a homozygous HPSE2 mutation changing asparagine 543 to isoleucine. The asparagine, located in the carboxy-terminus, is also highly conserved between vertebrate orthologs, 12 but it is not predicted to be glycosylated.…”