Figure 1.

FAME is caused by similar pentameric repeat expansion in six different genes (STARD7, YEATS2, RAPGEF2, MARCHF6, SAMD12, TNRC6A) located on different chromosomes. These expansions always occur at a polymorphic short tandem repeat (microsatellite) site initially composed of TTTTA motifs (in green) in healthy individuals (on the left). This microsatellite is usually adjacent to one or more Alu elements. Pathogenic repeat expansions (on the right) always include a TTTCA repeat insertion (in blue) that likely corresponds to the disease-associated part of the expansions and is mainly located at the 3′ end of the expansion. Configurations with this insertion in a more central position have also been described in SAMD12. All expansions are intronic and are likely transcribed as part of pre-mRNA transcripts. They could lead to a toxic RNA able to accumulate and trap RNA-binding proteins, although this remains to be demonstrated.