Mutations in HPSE2 cause urofacial syndrome.
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.
Daly
Sarah B
SB
Genetic Medicine, St. Mary's Hospital, Manchester Academic Health Sciences Centre (MAHSC), School of Biomedicine, University of Manchester, Manchester M13 9WL, UK.
Urquhart
Jill E
JE
Hilton
Emma
E
McKenzie
Edward A
EA
Kammerer
Richard A
RA
Lewis
Malcolm
M
Kerr
Bronwyn
B
Stuart
Helen
H
Donnai
Dian
D
Long
David A
DA
Burgu
Berk
B
Aydogdu
Ozgu
O
Derbent
Murat
M
Garcia-Minaur
Sixto
S
Reardon
Willie
W
Gener
Blanca
B
Shalev
Stavit
S
Smith
Rupert
R
Woolf
Adrian S
AS
Black
Graeme C
GC
Newman
William G
WG
D001921:Brain / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D002874:Chromosome Mapping; D002879:Chromosomes, Human, Pair 10; D019066:Facies; D005260:Female; D005808:Genes, Recessive; D005966:Glucuronidase / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008297:Male; D008958:Models, Molecular; D009132:Muscles / Q000378:metabolism; D009154:Mutation; D010375:Pedigree; D013577:Syndrome; D001743:Urinary Bladder / Q000378:metabolism; D014570:Urologic Diseases / Q000235:genetics*; D000099175:Heparanase
D005966:Glucuronidase; D000099175:Heparanase