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N Engl J Med. 2013 Aug 15;369(7):621-9. doi: 10.1056/NEJMoa1214479. Epub 2013 Jul 17.

Mutations in DSTYK and dominant urinary tract malformations.

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Divisions of Nephrology (S.S.-C., R.V.S., N.P., K.E.B., S.N.N., B.J.P., P.L.W., M.V., F.L., R.S., N.P., N.K., K.K., Q.A.-A., A.G.G.) and Pediatric Nephrology (P.L.W.) and the Department of Pathology (V.D.D.), Columbia University, and the Department of Medicine, St. Luke's-Roosevelt Hospital Center (S.S.-C.), New York; the Department of Genetics, Howard Hughes Medical Institute, and Yale Center for Mendelian Genomics, Yale University, New Haven, CT (M.C., M.S., R.P.L.); the Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, South Korea (M.C.); the Division of Nephrology, Dialysis, and Transplantation (M.B., F.L., G.C., A.C., M.D., C.M., G.P., G.M.G.) and Laboratory of Molecular Genetics (G.S., R.R.), Istituto Giannina Gaslini, the Division of Nephrology, Department of Internal Medicine (M.B.), and Dipartimento di Neuroscienze, Riabilitazione, Oftalmologia, Genetica e Scienze Materno Infantili (R.R.), University of Genoa, and IRCCS San Martino-IST (M.B.), Genoa; Cattedra di Nefrologia, Università di Brescia, Seconda Divisione di Nefrologia Azienda Ospedaliera Spedali Civili di Brescia Presidio di Montichiari, Brescia (C.I., F.S.); the Department of Clinical Medicine, Nephrology, and Health Sciences, Unit of Nephrology, University of Parma, Parma (B.B., S.G., L.A.); the Department of Medical and Surgical Sciences, University of Foggia, Foggia (M.G.); the Department of Emergency and Organ Transplantation, University of Bari, Bari (L.G.); and the Division of Nephrology and Dialysis, Hospital of Alghero, Alghero (D.C.) - all in Italy; the Nephrology Division, Massachusetts General Hospital (Y.L., I.A.D.), and Department of Genetics, Harvard Medical School (I.A.D.), Charlestown, MA; University Children's Hospital, Medical School of Skopje, Skopje, Macedonia (V.J.L., N.R.-B., Z.G., V.T.); the Department of Medical Genetics, Poznan University of Medical Sciences, Poznan, Poland (A.M.-K., A.L.-B.); and the Department of Pediatrics, University Hospital of Split (D.K.V., M.S.), and the Department of Anatomy, Histology, and Embryology (K.V., M.S.-B.), School of Medicine (M.S.), University of Split, Split, Croatia.
Contributed equally



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.


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.


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 knockdown in human embryonic kidney cells inhibited FGF-stimulated phosphorylation of extracellular-signal-regulated kinase (ERK), the principal signal downstream of receptor tyrosine kinases.


We detected independent DSTYK mutations in 2.3% of patients with congenital abnormalities of the kidney or urinary tract, a finding that suggests that DSTYK is a major determinant of human urinary tract development, downstream of FGF signaling. (Funded by the National Institutes of Health and others.).

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