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 8 tandemly repeated 22 bp segment harboring the wild-type or variant FOX-binding site and FOXA2 expression vector, showing a positive transactivation function for the wild-type 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.