Mitochondrial gene variation in type 2 diabetes mellitus: detection of a novel mutation associated with maternally inherited diabetes in a Chinese family.

OBJECTIVE: To explore the relationship between type 2 diabetes mellitus and the mutation(s) in mitochondrial DNA.
METHODS: According to the previous literature, the fragment of mitochondrial DNA from nucleotide 3153 to 3551, which had shown high frequency of point mutation, was scanned with the technique of polymerase chain reaction--single strand conformation polymorphism (PCR-SSCP) in Chinese normal control, type 2 diabetic population, and 12 families suffered from maternally inherited type 2 diabetes mellitus. Direct sequencing was applied to detect the fragments with abnormal conformation.
RESULTS: No special band was found in SSCP electrophoreses in Chinese normal control, and only one subject (No. 81) of diabetic population indicated the abnormality in SSCP study, which was affirmed to be a silent point mutation of T to C at nucleotide 3336 inducing no change in amino acid (ATT-->ATC, Ile). Pedigree 25,001 was the only family that exhibited strongly different SSCP characteristic from the other 11 ones, which was confirmed to be caused by a single point mutation mt3285T-->C/T in the coding region of tRNA(Leu(UUR)) gene by the technique of direct sequencing.
CONCLUSIONS: The variation within mt DNA 3153-3551 is not the major cause of type 2 diabetes in Chinese population suffered from this disease in this study. The point mutation T-->C/T at the mitochondrial nucleotide 3285, which was found in pedigree 25,001, is located in the highly conservative region of tRNA(Leu(UUR)) gene. It is strongly suggested that this mutation cause the conversion in the 3-dimentional structure of tRNA(Leu(UUR)), which might disturb the normal translation and lead to the impairment in mitochondrial oxidative phosphorylation characterized by the defects of the polypeptides involved in the respiratory chain. Thus, insulin secretion deficiency and insulin resistance might occur.