OP-5：Studies of the genetic variability of the Pax4, Nkx6.1 and Nkx2.2 genes in Thai with maturity onset diabetes of the young (MODY)

 

Nattachet Plengvidhaya,

 

Maturity onset diabetes of the young (MODY), a monogenic subtype of type 2 diabetes, is characterized by autosomal dominant inheritance, early onset, and b cell dysfunction. To date, mutations in six different genes have been shown to cause MODY: HNF-4a/MODY1, glucokinase/MODY2, HNF-1a/MODY3, IPF-1/MODY4, HNF-1b/MODY5 and NeuroD1/MODY6. However, some families with this form of diabetes do not carry mutations in these genes; the additional MODY genes should exist. Most of the MODY genes, except the glucokinase gene, are transcription factors crucial for normal development and function of pancreatic b-cell highlighted the role of transcription factors in the development of diabetes. Pax4, Nkx6.1 and Nkx2.2 are transcription factors that have been shown to play an important role in b cell development and function suggesting that Pax4, Nkx6.1, and Nkx2.2 genes may be candidate genes for MODY.

 

To investigate whether genetic variability in the Pax4, Nkx6.1 and Nkx2.2 genes may be associated with MODY in Thai population, we screened the coding regions for sequence variations by PCR-SSCP analysis and direct sequencing in 46 probands from families with clinical diagnosis of MODY unlinked to known MODY genes. We identified five different mutations in the Pax4, Nkx6.1, and Nkx2.2 genes in five different probands: Pax4 R31Q, R164W and IVS7-1GgA; Nkx6.1 M31I; Nkx2.2 3'UTR+12AgG. These mutations were not detected in 74 normal controls (148 chromosomes). The R164W mutation of the Pax4 gene seems to cosegregate with diabetes within family as it is inherited from affected parent although two sisters who had impaired glucose tolerance did not carry this mutation. We also found several single nucleotide polymorphisms (SNPs) in these genes as summarized in table 1. Among them, the frequency of R192H in the Pax4 gene were significantly higher in MODY than in control group (p<0.01). Our results indicate that genetic variability in the Pax4, Nkx6.1 and Nkx2.2 genes may not be a common cause of MODY in Thai. We are currently collecting the DNA from family members for studying the transmission of all the variants identified within the families.