Mutations in DSTYK and Dominant Urinary Tract Malformations

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.) Exome sequencing in a family with autosomal dominant congenital urinary tract malformations showed a mutation in dual serine-threonine and tyrosine protein kinase (DSTYK), confirmed in other, unrelated patients, identifying a major determinant of human urinary tract development. Congenital malformations of the kidney and urinary tract contribute to 23% of birth defects(1),(2) and account for 40 to 50% of pediatric cases and 7% of adult cases of end-stage renal disease (ESRD) worldwide.(3),(4) These disorders are genetically heterogeneous and encompass a wide range of anatomical defects, such as renal agenesis, renal hypodysplasia, ureteropelvic junction obstruction, or vesicoureteral reflux.(5) Mutations in genes that cause syndromic disorders, such as HNF1B and PAX2 mutations, are detected in only 5 to 10% of cases.(6),(7) Familial forms of nonsyndromic disease have been reported, further supporting genetic determination(8),(9); however, owing ...