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For the first time, mutations in a specific gene—DSTYK—have been linked to nonsyndromic malformations of the kidney and urinary tract. The discovery of a gene responsible for congenital urinary tract defects advances our understanding of these abnormalities, which are the most common cause of paediatric kidney failure.

Previously, the genetic causes of such disorders (which include renal agenesis, ureteropelvic junction obstruction and vesicoureteral reflux) have been hard to find owing to genetic heterogeneity and the lack of families with a sufficient number of affected individuals. The development of new sequencing methods has brought fresh possibilities. “With advances in technology, we can sequence all the protein coding regions of the genome (the exome) in one shot to identify mutations even in small families,” says Ali Gharavi, who led the study.

Researchers performed genome-wide linkage analysis in a Sardinian family with an autosomal dominant disorder. Seven family members were considered to be affected based on imaging studies, three of whom were diagnosed with end-stage renal disease at a young age owing to ureteropelvic junction obstruction. Five regions of the genome were found to be shared among the affected patients, corresponding to 55.44 Mb of the genome and containing 645 protein-coding genes. Exome sequencing, used to evaluate all of these genes simultaneously in two patients, revealed that DSTYK was the gene of interest. A heterozygous splice-site mutation was found in all affected individuals.

...this finding provides an opportunity for making precise diagnosis...

Gharavi and colleagues analysed DSTYK in 311 additional patients with congenital malformations of the urinary tract and kidney, finding independent mutations (nonsense and splice-site mutations) in seven patients. Thus, DSTYK mutations account for 2.3% of urinary tract defects in humans. For comparison, the researchers examined the incidence of DSTYK mutations in the National Heart, Lung, and Blood Institute database of exome data. Only 0.3% of white people were found to have DSTYK missense mutations at conserved positions, confirming the significant association between DSTYK and urinary tract abnormalities (OR 7.1; P = 0.0003).

So what is DSTYK? “Little was known about DSTYK at the time so we had to work for another year to figure out its function,” explains Gharavi. “Our data suggest that DSTYK is a kinase that mediates FGF signalling, which is known to be important for nephrogenesis.” In a series of experiments, the investigators demonstrated that DSTYK was highly expressed in the cell membranes of mesenchymal-derived cells of all major organs, and that loss of DSTYK in the zebrafish caused a number of developmental defects suggestive of FGF signal disruption.>

“For now, this finding provides an opportunity for making precise diagnosis, defining family members at risk and allowing for genetic counseling,” says Gharavi. “In the long term we want to define factors that are important for nephrogenesis in humans so we can improve diagnosis and treatment.”