A Novel PAX4 Mutation in a Japanese Patient with Maturity-Onset Diabetes of the Young

Maturity-onset diabetes of the young (MODY) is a genetically and clinically heterogeneous type of diabetes mellitus, characterized by early onset (often before 25 years of age) and absence of pancreatic autoimmunity markers. Paired-homeodomain transcription factor 4 (PAX4) functions as a transcriptional repressor and is involved in the differentiation of insulin-secreting beta-cells. Here we identified a novel PAX4 mutation in a Japanese patient with MODY. A 15-year-old, non-obese boy was admitted to our hospital because of polyuria and polydipsia. Laboratory evaluation showed an elevated fasting glucose level; however, islet cell antibodies and glutamic acid decarboxylase antibodies were not detected in the patient's serum. The proband's father had been diagnosed as having type 2 diabetes at age of 30 years. We therefore analyzed several candidate genes of MODY, and identified a novel mutation of a 39-base heterozygous deletion in exon 3 (c.374-412 de139) of PAX4 in the proband and his father. This mutation may cause exon 3 skipping that results in a frameshift, thereby producing a premature stop codon in exon 5. As this mutant PAX4 lacks a part of the homeodomain that is critical for binding to the target gene, this mutant was thought to lose the transcriptional repressor function. As expected, luciferase-reporter assays revealed that the mutant PAX4 could not repress the activities of insulin and glucagon gene promoters, unlike the wild-type PAX4 that repressed the promoter activities. The present study demonstrates that a novel mutation of PAX4 is likely to be associated with diabetes in this Japanese family.