THE FIRST PATHOGENIC MITOCHONDRIAL METHIONINE TRANSFER-RNA POINT MUTATION IS DISCOVERED IN SPLENIC LYMPHOMA

We describe a novel point mutation in the mitochondrial DNA transfer R NA methionine gene, a G-to-A transition at position 4450, in a patient with a splenic lymphoma with villous lymphocytes, The patient's lymph ocytes were remarkable by the presence of large cytoplasmic inclusions demonstrated as abnormal mitochondria by electron microscopy and led to the discovery of the mutation using denaturing gradient gel electro phoresis as a screening procedure, The pathogenic potential of the mut ation was clearly established by the following criteria, It was absent in a control population, It involves a nucle otide that is highly con served along the phylogenetic tree, The mutation was heteroplasmic and , when present in a high proportion, was associated with morphological alterations of the mitochondria, with defects of respiratory chain co mplexes activities and with a decrease in the mitochondrially encoded cytochrome c oxidase subunit II. Transfer of the mutation in RhoO cell s allowed to demonstrate its association with a severe respiratory cha in dysfunction, However, although the pathogenicity of the mutation wa s clearly demonstrated, its link With the patient disease remained dis putable, (C) 1997 Wiley-Liss, Inc.