Novel HK1 intronic variant in congenital hyperinsulinism: impaired transactivation function for FOXA2

Recent studies have revealed multiple genetic variants affecting a highly conserved ∼50 bp region encompassing the putative NFAT, NKX2, and FOX binding sites in HK1 intron 2 in congenital hyperinsulinism (CHI) with aberrant HK1 expression in β cells. We identified a novel "likely pathogenic" variant (NC_000010.11:g.69348930T>C) within the FOX-binding site in a Japanese boy and his father with CHI. Furthermore, we performed luciferase assays using HEK293T cells transfected by luciferase reporter vector with eight tandemly repeated 22 bp segment harboring the wildtype or variant FOX-binding site and FOXA2 expression vector, showing a positive transactivation function for the wildtype binding site and an impaired transactivation function for the variant binding site. While it remains unknown how HK1 intronic variants lead to aberrant HK1 expression in β cells and resultant development of CHI, the results indicate that the intron variant is associated with functional alteration in terms of FOXA2 stimulation.