Single-stranded conformational polymorphism analysis of the mitochondrial glycerol phosphate dehydrogenase gene in NIDDM.

Because the activity of mitochondrial glycerol phosphate dehydrogenase (mGPD) in the pancreatic 3-cell is normally among the highest of the body, but is low in the pancreatic islets of numerous rodent models of NIDDM and is reported to be low in the islets of the few humans studied with NIDDM (1,2), it has been questioned whether mGPD might be a diabetes candidate gene. Linkage studies have failed to find an association between mGPD and NIDDM in Caucasians (3) and Mexican Americans (4), which suggests that mutations in mGPD are not a common cause of NIDDM. Since NIDDM is a multifactorial and heterogeneous disorder, it is possible that abnormalities in many individual genes influencing reactions that are important for the maintenance of normal glucose homeostasis in the (3-cell will be found in a low percentage of individuals with NIDDM. With this idea in mind, conditions for using single-stranded conformational polymorphism (SSCP) analysis of the mGPD gene were developed to use this method to screen for mutations in this gene. Initial screening of all 18 exons of mGPD in 39 Caucasian individuals with NIDDM (age range at diagnosis, 31-88 years; mean ± SD, 51 ± 13 years) from the University of Wisconsin was unremarkable, except for exon 6 of subject 30 (a 63year-old nonobese man with an onset of NIDDM at age 53, who also received treatment for hyperlipidemia and hypertension). Two sisters, ages 69 and 72, and one brother, age 63, of subject 30, none of whom had diabetes, also possessed the mutation as judged by SSCP analysis. DNA sequencing showed that all four individuals were heterozygous for the mutation. DNA available at the Rockefeller University from a separate set of 48 NIDDM subjects with an early or late onset