About the “pathological” role of the mtDNA T3308C mutation...

Numerous mtDNA mutations have been associated with the mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes (MELAS) syndrome (MIM 540000). These include transitions at nucleotide positions (nt) 1642, 3243, 3252, 3256, 3271, 3291, 3308, and 9957, and a 4-bp deletion beginning at nt 14787. For some of these mutations (A3243G, C3256T, and T3271C), the causal relationship with the phenotype has been confirmed, whereas for others, the status is still provisional (MITOMAP). The T3308C mutation in the NADH dehydrogenase subunit 1 (ND1) is a member of the “provisional” group and was described in a Spanish subject affected by MELAS and bilateral striatal necrosis. This mutation changes the highly conserved methionine 1 to a threonine, was heteroplasmic in both the proband and her asymptomatic mother, and was absent in 130 normal and other-disease controls. More recently, a homoplasmic T3308C mutation has also been reported in a colorectal tumor, in which it was associated with two other somatic homoplasmic transitions, T710C and T1738C. It has been suggested that these mutations could have a functional effect in mitochondrial selection (Polyak et al. Polyak et al., 1998). However, doubts about the pathological significance of the T3308C mutation have been raised by a study involving 37 Portuguese patients with a clinical phenotype of mitochondrial encephalomyopathies and 150 Portuguese control subjects. The T3308C mutation was observed in two patients and in four controls. In all cases it was homoplasmic. To better define the role of this putative pathological mutation, here we did a detailed analysis of the mtDNA background on which the T3308C had been reported