Mutations in SOX17 are associated with congenital anomalies of the kidney and the urinary tract

Stefania Gimelli (1) , Gianluca Caridi (2) , Silvana Beri (3) , Kyle Mccracken (4) , Renata Bocciardi (5) , Paola Zordan (6) , Monica Dagnino (7) , Patrizia Fiorio (8) , Luisa Murer (9) , Elisa Benetti (9) , Orsetta Zuffardi (10) , Roberto Giorda (3) , James M Wells (4) , Giorgio Gimelli (11) , Gianmarco Ghiggeri (12)

1 Department of Obstetrics and Gynecology
2 Laboratorio di Fisiopatologia dell'Uremia
3 IRCCS E. Medea
4 Division of Developmental Biology
5 Laboratorio di Genetica Molecolare
6 Division of Regenerative Medicine, Stem Cells and Gene Therapy
7 Laboratorio di Fisiopatologia dell'Uremia
8 Laboratorio di Citogenetica
9 Unità di Nefrologia, Dialisi e Trapianto, Dipartimento di Pediatria
10 Biologia Generale e Genetica Medica
11 Laboratorio di citogenetica
12 Divisione di Nefrologia

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 8 patients with CAKUT (7 vesico-ureteric reflux,1 pelvic obstruction). One mutation, p.Y259N, recurred in 6 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-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-Y259N mutation as a causative factor in CAKUT.

Mots clés: Life Sciences

Stefania Gimelli, Gianluca Caridi, Silvana Beri, Kyle Mccracken, Renata Bocciardi, et al.. Mutations in SOX17 are associated with congenital anomalies of the kidney and the urinary tract. Human Mutation, 2010, 31 (12), pp.1352. ⟨10.1002/humu.21378⟩. ⟨hal-00599471⟩