Mutations in SOX17 are associated with congenital anomalies of the kidney and the urinary tract.
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.
Biologia Generale e Genetica Medica, Università di Pavia, Pavia, Italy; Service of Genetic Medicine, University Hospitals of Geneva, Geneva, Switzerland.
Stefania
S
Gimelli
Gianluca
G
Caridi
Silvana
S
Beri
Kyle
K
McCracken
Renata
R
Bocciardi
Paola
P
Zordan
Monica
M
Dagnino
Patrizia
P
Fiorio
Luisa
L
Murer
Elisa
E
Benetti
Orsetta
O
Zuffardi
Roberto
R
Giorda
James M
JM
Wells
Giorgio
G
Gimelli
Gian Marco
GM
Ghiggeri
D002675:Child, Preschool; D055028:Comparative Genomic Hybridization; D000013:Congenital Abnormalities / Q000235:genetics*; D005190:Family; D005260:Female; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007668:Kidney / Q000002:abnormalities*; D008297:Male; D050505:Mutant Proteins / Q000235:genetics / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D011247:Pregnancy; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D055760:SOXF Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014551:Urinary Tract / Q000002:abnormalities*
D050505:Mutant Proteins; D012333:RNA, Messenger; C109188:SOX17 protein, human; D055760:SOXF Transcription Factors