Programmpunkt

15:15–15:30

Titel: Heterozygous DACT1 variants impacting DVL2 binding in patients with kidney anomalies and features of Townes-Brocks syndrome 2
ID: W9-006
Art: Invited talk
Redezeit: 15 min
Session: Workshop 9
Monogenic Syndromes

Referent: Esra Kesdiren (Hannover/DE)


Abstract - Text

Abstract-Text

Despite recent efforts, most patients with congenital anomalies of the kidney and urinary tract (CAKUT) remain genetically unsolved. In search of novel genes associated with syndromic CAKUT in humans, we applied whole-exome sequencing to a patient with renal anomalies, i.e. left-sided kidney agenesis and right-sided duplex kidney, who also had extrarenal abnormalities, e.g. anorectal and sacral as well as brain anomalies. In this syndromic CAKUT patient, we identified a very rare heterozygous missense variant in the DACT1 (dishevelled binding antagonist of beta catenin 1) gene. DACT1 encodes an intracellular signaling protein that interacts with dishevelled family proteins and negatively modulates WNT signaling by promoting DVL2 (dishevelled segment polarity protein 2) degradation. Our patient"s features overlapped Townes-Brocks syndrome 2 (TBS2), previously described in a family carrying a DACT1 nonsense variant, and those of Dact1-deficient mice. Therefore, we assessed the role of DACT1 in the pathogenesis of syndromic CAKUT by whole-exome and targeted DACT1 sequencing of 208 further CAKUT families. Altogether, seven very rare heterozygous DACT1 missense variants, predominantly likely pathogenic and almost exclusively maternally inherited, were detected in a total of eight families with renal agenesis, dysplasia, or hypoplasia and TBS2 features of 209 CAKUT families (3.8%), significantly more frequently than in controls. All DACT1 variants were located in the DVL2 interaction region, and biochemical characterization using co-immunoprecipitation revealed reduced mutant DACT1-DVL2 binding, suggesting that the identified variants act as hypomorphs. By RNA in situ hybridization on murine embryo sections at different developmental stages, Dact1 mRNA expression was detected in various organs that were affected by anomalies in the patients, including the kidney, anal canal, vertebrae, and brain. CRISPR/Cas9-derived knockout of Dact1 impaired tubule formation of murine inner medullary collecting duct cells, a cellular model for tubulomorphogenesis. In summary, we provide evidence that heterozygous hypomorphic DACT1 variants cause CAKUT in patients with features overlapping TBS2. (DFG grant no. KO5614/2-1 and MA9606/1-1)