Mutations in HPSE2 Cause Urofacial Syndrome

Abstract

Urinary voiding dysfunction in childhood, manifesting as incontinence, dysuria, and urinary frequency, is a common condition. Urofacial syndrome (UFS) is a rare autosomal recessive disease characterized by facial grimacing when attempting to smile and failure of the urinary bladder to void completely despite a lack of anatomical bladder outflow obstruction or overt neurological damage. UFS individuals often have reflux of infected urine from the bladder to the upper renal tract, with a risk of kidney damage and renal failure. Whole-genome SNP mapping in one affected individual defined an autozygous region of 16 Mb on chromosome 10q23-q24, within which a 10 kb deletion encompassing exons 8 and 9 of HPSE2 was identified. Homozygous exonic deletions, nonsense mutations, and frameshift mutations in five further unrelated families confirmed HPSE2 as the causative gene for UFS. Mutations were not identified in four additional UFS patients, indicating genetic heterogeneity. We show that HPSE2 is expressed in the fetal and adult central nervous system, where it might be implicated in controlling facial expression and urinary voiding, and also in bladder smooth muscle, consistent with a role in renal tract morphology and function. Our findings have broader implications for understanding the genetic basis of lower renal tract malformations and voiding dysfunction.

<b><i>HPSE2</i></b> Mutations in Urofacial Syndrome, Non-Neurogenic Neurogenic Bladder and Lower Urinary Tract Dysfunction

“…Four-year-old twin brothers with UFS were homozygous for this variant that was reported earlier [13]. Both presented with urosepsis at nine and 18 months of age and were found to have bladder dysfunction with bilateral VUR.…”

“…However, UFS-causing gene mutations were first reported by two groups in 2010 [13,14]. To date, 10 different HPSE2 gene mutations have been reported in a total of 28 UFS patients from 17 families in different studies [13,14,15,16].…”

“…Mutation analysis of our patients was performed in our center except for a family with UFS; this family had been previously genetically studied by Daly et al [13]. Genomic DNA was extracted from peripheral blood using a standard phenol chloroform method.…”

“…In recent years, biallelic mutations of HPSE2 (chromosome 10q24.2) (MIM 236730) and LRIG2 (chromosome 1p13.2) (MIM 615112) have been reported in UFS patients [13,14,15,16,17]. Non-neurogenic neurogenic bladder (NNNB) also called Hinman-Allen syndrome has a bladder identical to that seen with UFS without typical facial features, for which the pathogenesis is unknown.…”

“…In recent years, with reported cases of NNNB in early childhood, genetic factors have been suggested in the pathogenesis since it is not always an acquired disease [18,19,20]. Expression of HPSE2 and LRIG2 genes in the bladder further suggests that mutations in these genes might be responsible for other bladder pathologies [13,17]. The aim of this study was to analyse HPSE2 mutations in patients with UFS and NNNB or severe lower urinary tract dysfunction (LUTD) without abnormal facial expression.…”