1. Mutations in HPSE2 Cause Urofacial Syndrome
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Berk Burgu, Sarah B. Daly, Stavit A. Shalev, William G. Newman, Adrian S. Woolf, David A. Long, Bronwyn Kerr, Ozgu Aydogdu, Jill E. Urquhart, Sixto García-Miñaur, Graeme C.M. Black, Richard A. Kammerer, Emma Hilton, Malcolm A. Lewis, Helen M. Stuart, Willie Reardon, Blanca Gener, Rupert Smith, Edward A. McKenzie, Murat Derbent, and Dian Donnai
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Male ,Models, Molecular ,Pathology ,urologic and male genital diseases ,Genetics(clinical) ,Child ,Genetics (clinical) ,Glucuronidase ,Facies ,Muscles/metabolism ,Kidney ,Urinary bladder ,Urologic Diseases/*genetics ,Urofacial syndrome ,Muscles ,Brain ,Chromosome Mapping ,Syndrome ,Pedigree ,medicine.anatomical_structure ,Child, Preschool ,Female ,medicine.symptom ,Erratum ,Urologic Diseases ,medicine.medical_specialty ,Urinary system ,Urinary Bladder ,Nonsense mutation ,Genes, Recessive ,Biology ,Frameshift mutation ,Report ,Internal medicine ,Manchester Institute of Biotechnology ,medicine ,Genetics ,Dysuria ,Brain/metabolism ,Humans ,Glucuronidase/chemistry/*genetics/metabolism ,Urinary Bladder/metabolism ,Genetic heterogeneity ,Chromosomes, Human, Pair 10 ,medicine.disease ,ResearchInstitutes_Networks_Beacons/manchester_institute_of_biotechnology ,Endocrinology ,Mutation - 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. © 2010 The American Society of Human Genetics.
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