ESR 3: The identification of HNF1B modifier genes in renal disease

Supervisor: Marco Pontoglio

PhD Student: Eleonora Del Fiore

Short Summary

Hepatocyte nuclear factor-1β (HNF1B) is a bookmarking transcription factor expressed in liver, pancreas, intestine and kidneys. HNF1B mutations are frequently the cause of monogenic syndromic CAKUT (Congenital Abnormalities of the Kidney and the Urogenital Tract) which often lead to renal failure in children.

The disease is characterized by a wide repertoire of renal dysfunction, which varies from failure in kidney development (kidney agenesis), defective cell differentiation (dysplasia), defective cell expansion (hypoplasia), and formation of cysts.

Patients presenting HNF1B heterozygous mutation show a large phenotypic variability. The very same familiar mutations can result in different phenotypes, varying from asymptomatic to severe kidney dysfunctions.

In general, HNF1B patients usually carry heterozygous null mutations. It is therefore supposed that these patients suffer from haploinsufficiency. In other words, it is believed that HNF1B patients may carry a residual HNF1B activity close to a critical threshold. We hypothesize that at least part of the variability generally observed in HNF1B patients, might be explained by the segregation of modifier genes that, in turn, may influence HNF1B residual activity, affecting the resulting phenotype.

Scientific strategy

ln this study, we will try to identify potential modifier gene variants that might affect the residual HNFlB activity in patients. To identify genes whose KO impact on HNFlB transcriptional activity we will perform a genome-wide CRISPR interference screening. ln a second step, we will first consider discordant duos: patients carrying the same familial mutation but presenting with discordant extreme phenotypes. The presence of segregating variants in candidate modifier genes will be identified in these discordant duos. Finally, we will verify the actual effect of gene variants observed in discordant duos, on the activity of HNFlB.

Expected result

  • lmproving our understanding of the molecular mechanisms that account for the heterogeneous phenotype of HNFlB deficiency;
  • Identification of the genetic variants responsible for the differential phenotype linked to HNFlB deficiency;
  • Development of diagnostic tools; A methodological proof of principle for approaching other genetic human diseases.