Could changes in one gene help explain why some children are born with both kidney and other organ abnormalities?

Details

Most patients with congenital anomalies of the kidney and urinary tract (CAKUT) still lack a genetic explanation. To look for new genes associated with human CAKUT, researchers used whole-exome sequencing in a patient with kidney, anorectal, spinal, and brain anomalies. They identified a rare heterozygous missense variant—a change in one copy of the gene that changes an amino acid—in DACT1 (dishevelled binding antagonist of beta catenin 1), which encodes a cytoplasmic mediator of WNT signaling.

The patient's features overlapped with Townes–Brocks syndrome 2 (TBS2), previously described in a family carrying a DACT1 nonsense variant, and with features of Dact1-deficient mice. These similarities prompted the researchers to assess DACT1's role in CAKUT pathogenesis.

Overall, very rare non-silent DACT1 variants, defined by a minor allele frequency ≤ 0.0005, were detected in eight of 209 CAKUT families (3.8%). This was significantly more frequent than in controls (1.7%). All seven distinct DACT1 missense variants were located in the region that interacts with DVL2 (dishevelled segment polarity protein 2). They were predominantly classified as likely pathogenic and were exclusively maternally inherited. Biochemical characterization showed that mutant DACT1 bound less strongly to DVL2.

Patients carrying DACT1 variants had kidney agenesis, duplex kidneys or cystic/multicystic dysplastic or hypodysplastic kidneys with hydronephrosis, together with TBS2 features. During mouse development, Dact1 was expressed in organs affected in patients with DACT1 variants, including the kidney, anal canal, vertebrae, and brain.

In a branching morphogenesis assay, tubule formation was impaired in murine inner medullary collecting duct cells with CRISPR/Cas9-induced Dact1−/− knockout. The researchers concluded that their findings provide evidence that heterozygous hypomorphic—partially function-reducing—DACT1 variants cause CAKUT and other TBS2 features, including anomalies of the skeleton, brain, distal digestive tract, and genital tract.