The different substrate specificities described above may explain why MLH1 and MSH2 are the most important predisposing genes for LS (their protein products are obligatory components in all types of heterodimers, Fig. 1), followed by MSH6 and PMS2, whereas MLH3 mutations are rare (functionally redundant with PMS2), and no LS-predisposing germline mutations are known for MSH3 (functionally redundant with MSH6). Here, MSH3 is linked to Leigh syndrome.