Mutation Linked to Congenital Urinary Tract Defects

A specific genetic mutation has been linked to a nonsyndromic form of urinary tract malformation.

A genetic mutation has been identified that causes congenital malformations of the kidney and urinary tract, a common form of birth defect and the most common cause of kidney failure in children.


Scientists at the Columbia University Medical Center (New York, NY, USA) studied a Sardinian family with congenital malformations of the kidney and urinary tract. Several family members had experienced kidney failure at a young age. They used a recently developed tool of exome gene sequencing that sequences only the coding parts of the genome, and identified a mutation in a gene called dual serine/threonine and tyrosine protein kinase (DSTYK) in all of the affected family members.

The investigators then screened 311 unrelated individuals with urinary tract defects from centers throughout Europe and found seven other patients with DSTYK mutations. Exome sequencing identified a single, rare, deleterious variant within these linkage intervals, a heterozygous splice-site mutation in the DSTYK gene. This variant, which resulted in aberrant splicing of messenger ribonucleic acid (mRNA), was present in all affected family members.

Immunohistochemical testing was performed with the use of anti-DSTYK antibody (Santa Cruz Biotechnology, Dallas, TX, USA) on paraffin-embedded tissues with the use of heat-induced antigen retrieval.

Some cases of congenital urinary tract defects present with kidney failure at birth, while others are not evident until complications arise, sometimes not until years later. By defining a new form of disease, these findings will allow clinicians to make a precise molecular diagnosis and identify mutation carriers who may be at risk for complications. Ali G. Gharavi, MD, a professor of nephrology and lead author, said, “Exome gene sequencing is now the method of choice for diagnosis of congenital disorders of unknown cause. It is what enabled us to detect the mutation that was shared by all affected individuals in the Sardinian family.”

The scientists now plan to use the exome genome sequencing approach to study other patients and define additional forms of congenital urinary tract defects. They concluded that they had 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 fibroblast growth factor signaling. The study was published on July 17, 2013, in the New England Journal of Medicine (NEJM).

Related Links:
Columbia University Medical Center
Santa Cruz Biotechnology