1. Mutations in DSTYK and Dominant Urinary Tract Malformations
- Author
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Sanna-Cherchi, Simone, Sampogna, Rosemary V, Papeta, Natalia, Burgess, Katelyn E, Nees, Shannon N, Perry, Brittany J, Choi, Murim, Bodria, Monica, Liu, Yan, Weng, Patricia L, Lozanovski, Vladimir J, Verbitsky, Miguel, Lugani, Francesca, Sterken, Roel, Paragas, Neal, Caridi, Gianluca, Carrea, Alba, Dagnino, Monica, Materna-Kiryluk, Anna, Santamaria, Giuseppe, Murtas, Corrado, Ristoska-Bojkovska, Nadica, Izzi, Claudia, Kacak, Nilgun, Bianco, Beatrice, Giberti, Stefania, Gigante, Maddalena, Piaggio, Giorgio, Gesualdo, Loreto, Vukic, Durdica Kosuljandic, Vukojevic, Katarina, Saraga-Babic, Mirna, Saraga, Marijan, Gucev, Zoran, Allegri, Landino, Latos-Bielenska, Anna, Casu, Domenica, State, Matthew, Scolari, Francesco, Ravazzolo, Roberto, Kiryluk, Krzysztof, Al-Awqati, Qais, D'Agati, Vivette D, Drummond, Iain A, Tasic, Velibor, Lifton, Richard P, Ghiggeri, Gian Marco, and Gharavi, Ali G
- Subjects
Urologic Diseases ,Pediatric ,Congenital Structural Anomalies ,Human Genome ,Kidney Disease ,Biotechnology ,Genetics ,Clinical Research ,1.1 Normal biological development and functioning ,2.1 Biological and endogenous factors ,Underpinning research ,Aetiology ,Renal and urogenital ,Adult ,Animals ,Base Sequence ,Child ,Exome ,Female ,Gene Knockdown Techniques ,Genetic Linkage ,Genome-Wide Association Study ,Heterozygote ,Humans ,Infant ,Kidney ,Male ,Mice ,Molecular Sequence Data ,Mutation ,Pedigree ,RNA ,Small Interfering ,Receptor-Interacting Protein Serine-Threonine Kinases ,Urinary Tract ,Urogenital Abnormalities ,Young Adult ,Medical and Health Sciences ,General & Internal Medicine - Abstract
BackgroundCongenital 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.MethodsWe 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.ResultsLinkage 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.ConclusionsWe 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.).
- Published
- 2013