An intron mutation of HNF1A causes abnormal splicing and impairs its activity as a transcription factor

Mutations in HNF1A are associated with Maturity Onset Diabetes of the Young type 3 (MODY3) and most of them are in the coding region. Herein, we identified an intron mutation at the 6th nucleotide upstream of the end of intron 7 of HNF1A, named IVS7-6G > A, in a patient with early-onset diabetes. The "minigene" assay showed that IVS7-6G > A produced two aberrant mRNA variants translating into two truncated proteins: L502S fs* and G437A fs*, both affecting HNF1A transactivation domain (TAD). To determine functional consequences of IVS7-6G > A mutation, we made plasmids encoding truncated HNF1A containing different portions of HNF1A TAD and found that the TAD of HNF1A is important not only for its regulatory activities, but also for its nuclearization, and the residues 282-501 was more essential than 502-631. Our data suggested IVS7-6G > A impaired HNF1A splicing and may contribute to the pathogenesis of MODY3.