Heteroplasmic Mitochondrial DNA 3310 Mutation in NADH Dehydrogenase Subunit 1 Associated With Type 2 Diabetes, Hypertrophic Cardiomyopathy, and Mental Retardation in a Single Patient

The patient of this letter is a 57-year-old Japanese man with type 2 diabetes and mental retardation with maternal inheritance. The younger of his two sisters was healthy. An echocardiography and a myocardial biopsy revealed hypertrophic cardiomyopathy in the patient. Electron microscopic examination showed a marked increase of mitochondria and abnormal cristae in the myocardial fibers. Autopsy revealed both decrease and atrophy of pancreatic islets of Langerhans. Immunohistochemical staining showed a selective decrease of β-cells. Based on these findings, mitochondrial disease was suspected.

The mtDNA of the patient and his two sisters was studied by cloning and sequencing. Three unique point mutations were found in the patient’s lymphocytes. Two point mutations (C11215T and A15874G) were silent. The other mutation was C3310T in the ND1 gene. Two clones of mtDNA without the C3310T point mutations were obtained from the patient’s pancreas. However, all mtDNA extracted from the patient’s other tissues and his sisters’ lymphocytes had this mutation. None of the mtDNAs extracted from lymphocytes from 97 patients with type 2 diabetes and 82 normal control subjects that were evaluated by PCR-restriction fragment length polymorphism (PCR-RFLP) had this mutation. Informed consent was obtained from all participants.

The ND-1 gene encodes the NADH dehydrogenase (complex I) subunit 1. The C3310T point mutation replaces the hydrophobic amino acid proline with the hydrophilic serine. Other mutations in this region have been reported to be associated with diabetes (1,2) and Leber’s hereditary optic neuropathy (3). All reported mtDNA point mutations in this region have been homoplasmic. It has been assumed that other unknown pathogenic mtDNA changes, nuclear DNA changes, or environmental factors are involved in disease causation (1).

We obtained two mtDNA samples without the mutation from the patient, suggesting that the C3310T point mutation is heteroplasmic and the single pathogenic gene. However, other samples, even from the healthy sister, had only mutant mtDNA. Therefore, other factors cannot be ruled out. Since this mutation was not detected by PCR-RFLP, it is likely to occur rarely.