Mutations in DSTYK and Dominant Urinary Tract Malformations

作者：Simone Sanna‐Cherchi, Rosemary V. Sampogna, Natalia Papeta, Katherine Burgess, Shannon N. Nees, Benjamin J. Perry, Monica Young Choi, Monica Bodria, Ying Liu, Patricia L. Weng, Vladimir J. Lozanovski, Miguel Verbitsky, Francesca Lugani, Roel Sterken, Neal Paragas, Gianluca Caridi, Alba Carrea, M. Dagnino, Anna Materna‐Kiryluk, Giuseppe Santamaria, Corrado Murtas, Nadica Ristoska-Bojkovska, Claudia Izzi, Nilgun Kacak, B. Bianco, Stefania Giberti, Maddalena Gigante, Giorgio Piaggio, Loreto Gesualdo, D. Kosuljandic Vukic, Katarina Vukojević, Mirna Saraga‐Babić, Marijan Saraga, Zoran Gucev, L Allegri, Anna Latos‐Bieleńska, D. Casu, Matthew W. State, Francesco Scolari, Roberto Ravazzolo, Krzysztof Kiryluk, Qais Al‐Awqati, Vivette D. D’Agati, Iain A. Drummond, Velibor Tasić, Richard P. Lifton, Gian Marco Ghiggeri, Ali G. Gharavi · 发表于：New England Journal of Medicine · 年份：2013 · DOI：10.1056/nejmoa1214479 · 被引用次数：120 · 研究领域：Renal and related cancers、Pediatric Urology and Nephrology Studies、Renal cell carcinoma treatment

BACKGROUND: Congenital abnormalities of the kidney and the urinary tract are the most common cause of pediatric kidney failure. These disorders are highly heterogeneous, and the etiologic factors are poorly understood. METHODS: We performed genomewide linkage analysis and whole-exome sequencing in a family with an autosomal dominant form of congenital abnormalities of the kidney or urinary tract (seven affected family members). We also performed a sequence analysis in 311 unrelated patients, as well as histologic and functional studies. RESULTS: Linkage analysis identified five regions of the genome that were shared among all affected family members. Exome sequencing identified a single, rare, deleterious variant within these linkage intervals, a heterozygous splice-site mutation in the dual serine-threonine and tyrosine protein kinase gene (DSTYK). This variant, which resulted in aberrant splicing of messenger RNA, was present in all affected family members. Additional, independent DSTYK mutations, including nonsense and splice-site mutations, were detected in 7 of 311 unrelated patients. DSTYK is highly expressed in the maturing epithelia of all major organs, localizing to cell membranes. Knockdown in zebrafish resulted in developmental defects in multiple organs, which suggested loss of fibroblast growth factor (FGF) signaling. Consistent with this finding is the observation that DSTYK colocalizes with FGF receptors in the ureteric bud and metanephric mesenchyme. DSTYK kno...