FIGURE 4.

Comprehensive analysis of GAN mutations. (A) Exon-intron structure of the GAN gene and domain organization of the encoded protein Gigaxonin, with a N-terminal BTB domain and a C-terminal Kelch domain (depicted in blue, linker is called BACK domain). Mapping of the 75 mutations (see also Supplementary Table 1 for details): missense mutation (red circle), nonsense mutations (black star), mutations at splicing sites (black triangle), deletions/insertion (blue triangle) and large deletion (blue line). (B) Pie charts depicting the effects of GAN mutations. Distribution of mutation types in patients (middle): 60% are missense mutations “ms,” 17.4% of nonsense mutations “ns,” 16% of deletions/insertions “del/ins,” and 6.6% mutations at donor/accepting splicing sites “sp.” Other pie charts indicate the predominance of severe forms associated with missense mutations (left) and truncations [(right), including “ns,” “sp,” “del/ins”], representing 67.7 and 93.3% of cases, respectively. On (right), flow chart showing the influence of mutations on severity. Black and red lines indicate, respectively that the patient bearing both mutations has a mild or severe form of the disease. As example, the R545H mutation leads to a severe phenotype when found homozygous, while it is attenuated by combination with R269W, which is severe when associated to I244Fs.