(HealthDay News) – Independent mutations have been identified in the dual serine-threonine and tyrosine protein kinase gene (DSTYK) in 2.3% of patients with congenital abnormalities of the kidney and urinary tract, according to a study published online July 17 in the New England Journal of Medicine.

Simone Sanna-Cherchi, MD, from Columbia University in New York City, and colleagues conducted genome-wide lineage analysis and whole-exome sequencing in seven affected family members with an autosomal dominant form of congenital abnormalities of the kidney or urinary tract. Sequence analysis and histologic and functional studies were also performed in 311 unrelated patients.

In linkage analysis, the researchers identified five regions of the genome that were shared among all affected family members. A single, rare, deleterious variant was identified in exome sequencing within these linkage intervals. The variant, which was present in all affected family members, was a heterozygous splice-site mutation in DSTYK that resulted in aberrant splicing of messenger RNA. In seven of the 311 unrelated patients, additional, independent mutations were identified in DSTYK. Knockdown in zebrafish resulted in multiple organ developmental defects, indicative of loss of fibroblast growth factor (FGF) signaling. In ureteric bud and metanephric mesenchyme, DTSYK colocalizes with FGF receptors. In human embryonic kidney cells, knockdown of DSTYK inhibited FGF-stimulated phosphorylation of extracellular-signal-regulated kinase.

“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,” the authors write.

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