A MUTATION IN THE TRANSFER RNALEU(UUR) GENE ASSOCIATED WITH THE MELAS SUBGROUP OF MITOCHONDRIAL ENCEPHALOMYOPATHIES

MITOCHONDRIAL encephalomyopathies are usually divided into three distinct clinical subgroups: (1) mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS); (2) myoclonus epilepsy associated with ragged-red fibres (MERRF); and (3) chronic progressive external ophthalmoplegia (CPEO) including Kearns-Sayre syndrome1-5. Large deletions of human mitochondrial DNA and a transition mutation at the mitochondrial transfer RNAlys gene give rise to CPEO including Kearns-Sayre syndrome6-8 and MERRF9,10, respectively. Here we report an A-to-G transition mutation at nucleotide pair 3,243 in the dihydrouridine loop of mitochondrial tRNALeu(UUR) that is specific to patients with MELAS. Because this mutation creates an Apal restriction site, we could perform a simple molecular diagnostic test for the disease. The mutation was present in 26 out of 31 independent MELAS patients and 1 out of 29 CPEO patients, but absent in the 5 MERRF and 50 controls tested. Southern blot analysis confirmed that the mutant DNA always coexists with the wild-type DNA (heteroplasmy). © 1990 Nature Publishing Group.