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Mutations in SOX17 are associated with congenital anomalies of the kidney and the urinary tract
Author(s) -
Gimelli Stefania,
Caridi Gianluca,
Beri Silvana,
McCracken Kyle,
Bocciardi Renata,
Zordan Paola,
Dagnino Monica,
Fiorio Patrizia,
Murer Luisa,
Benetti Elisa,
Zuffardi Orsetta,
Giorda Roberto,
Wells James M.,
Gimelli Giorgio,
Ghiggeri Gian Marco
Publication year - 2010
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.21378
Subject(s) - wnt signaling pathway , urinary system , kidney , kidney development , medicine , mutation , nephron , mutant , transcription factor , cancer research , biology , endocrinology , genetics , gene , embryonic stem cell
Congenital anomalies of the kidney and the urinary tract (CAKUT) represent a major source of morbidity and mortality in children. Several factors (PAX, SOX,WNT, RET, GDFN, and others) play critical roles during the differentiation process that leads to the formation of nephron epithelia. We have identified mutations in SOX17, an HMG‐box transcription factor and Wnt signaling antagonist, in eight patients with CAKUT (seven vesico‐ureteric reflux, one pelvic obstruction). One mutation, c.775T>A (p.Y259N), recurred in six patients. Four cases derived from two small families; renal scars with urinary infection represented the main symptom at presentation in all but two patients. Transfection studies indicated a 5–10‐fold increase in the levels of the mutant protein relative to wild‐type SOX17 in transfected kidney cells. Moreover we observed a corresponding increase in the ability of SOX17 p.Y259N to inhibit Wnt/β‐catenin transcriptional activity, which is known to regulate multiple stages of kidney and urinary tract development. In conclusion, SOX17 p.Y259N mutation is recurrent in patients with CAKUT. Our data shows that this mutation correlates with an inappropriate accumulation of SOX17‐p.Y259N protein and inhibition of the β‐catenin/Wnt signaling pathway. These data indicate a role of SOX17 in human kidney and urinary tract development and implicate the SOX17–p.Y259N mutation as a causative factor in CAKUT.Hum Mutat 31:1352–1359, 2010. © 2010 Wiley‐Liss, Inc.