Context: Six MODY genes have been discovered to date but account for a small proportion of MODY among Asians, suggesting the existence of other MODY genes in this racial group.

Objective: The aim of this study was to investigate whether genetic variants in PAX4, a crucial transcription factor in -cells development, contribute to MODY in Thais.

Design and Methods: We screened PAX4 coding sequences in 46 MODY probands without mutation in known MODY genes and in 74 non-diabetic controls using PCR-SSCP analysis followed by direct sequencing. Genotyping of variants identified was done by PCR-RFLP.

Results: Eight sequence differences were identified. Two novel variations (R164W and IVS7-1G>A) were found in two different probands. Neither was found in the 74 non-diabetic controls and in additional 270 healthy subjects of Thai origin. R164W segregated with diabetes in the family of the proband and in vitro studies showed that it impairs the repressor activity of Pax4 on the insulin and glucagon promoters. The remaining six variants were previously described and were observed in both groups. One of them, R192H, was three times as frequent in MODY probands than in 342 non-diabetic controls (MAF=0.196 vs. 0.064, p<0.00001). The same variant was associated with a younger age at diagnosis among 254 Thai subjects with adult-onset type 2 diabetes (44.6 ± 15 vs. 49.7 ± 11 yrs, p=0.048).

Conclusions: We have identified two possible pathogenic mutations of PAX4, R164W and IVS7-1G>A. For one of these, we have shown evidence of segregation with diabetes and a functional impact on Pax4 activity. SNP R192H might influence the age at onset of diabetes.