**4. Mutations in p97 associated with IBMPFD**

So far, only single amino acid substitutions in p97 have been identified from all the clinical IBMPFD specimens examined. Altogether, twenty missense mutations found in 13 different amino acid positions in p97 have been reported to be associated with the disease and the majority of them involve substitutions of arginine residues (Table 1) (http://www.molgen.ua.ac.be/FTDMutations). While more than half of these mutations are located in the N-domain (Ile27, Arg93, Arg95, Pro137, Arg155, Gly157 and Arg159), a few are found in the N-D1 linker region between the N- and D1-domains (Arg191 and Leu198) and in the D1 domain (Ala232, Thr262, Asn387 and Ala439). None has been found in the D2-domain. Among these, mutations at Arg155 are the most frequently observed in patients (Table 1). Interestingly, mapping these mutations onto the three-dimensional p97 structure in the ADP-bound form revealed that they all clustered at the interface between the N- and D1 domains (N-D1-interface, Fig. 1C).
