| | Mutation | Domain located | Disease | Biochemical defects |
| | R93C | N domain | IBMPFD | Impaired degradation of ERAD substrates (e.g., CFTR, tyrosinase) [55, 56]; restored the growth of yeast cdc48 mutant at 37°C [57]. |
| | R95G | N domain | IBMPFD | Increased bindings to Ufd1, Npl4, p47, Ataxin 3, and ubiquitylated substrates; reduced bindings to Ufd2, CAV1, and UBXD1; little effects on the bindings to Hrd1, Png1 [58–60]; altered response to nucleotide-triggered conformation change of the N domain [61, 62]; enhanced ATPase activity and polyQ aggregation; compromised degradation of the myosin chaperone UNC-45 and ERAD substrates [63, 64]; impaired proteasome activity; accumulation of ubiquitin conjugates and TDP-43; induced cell death [6, 63, 64]. |
| | P137L | N domain | IBMPFD | Abolished bindings to Ufd1, Npl4, and p47, but still bind gp78 [60]; reduced solubility and altered cellular localization; impaired ERAD [60, 64]. |
| R155H
The most prevalent mutation | N domain | IBMPFD and ALS | Increased bindings to Ufd1, Npl4, p47, Ataxin 3, and ubiquitylated substrates; reduced bindings to Ufd2, CAV1, UBXD1; little effects on the bindings to Hrd1, Png1 [58–60]; altered response to nucleotide-triggered conformation change of the N domain [61, 62]; enhanced ATPase activity and polyQ aggregation; compromised degradation of the myosin chaperone UNC-45; impaired ERAD, autophagy, and proteasome; accumulation of ubiquitin conjugates and TDP-43; induced cell death; mitochondria defects [6, 63–65]. |
| | R155S | N domain | IBMPFD | Enhanced bindings to Ufd1, Npl4, p47, and Ataxin 3 [59]. |
| | R155C | N domain | IBMPFD and ALS | Increased bindings to Ufd1, Npl4, p47, Ataxin 3, and ubiquitylated substrates [59]; enhanced ATPase activity and polyQ aggregation; impaired ERAD and proteasome; accumulation of ubiquitin conjugates and TDP-43; induced cell death; mitochondria defects [63–65]; rescued yeast cdc48 mutant [57]. |
| | R155P | N domain | IBMPFD | Increased bindings to Ufd1, Npl4, p47, and ubiquitylated substrates [59]; enhanced ATPase activity and polyQ aggregation; normal hexmer formation; altered conformation of the D2 ring; compromised degradation of ERAD substrates [61–63]; rescued yeast cdc48 mutant [57]. |
| | R159G | N domain | ALS | Compromised degradation of ERAD substrates [55, 56, 63]. |
| | R191Q | N-D1 linker | ALS and IBMPFD | Increased bindings to Ufd1, Npl4, p47, and ubiquitylated substrates [59]; enhanced ATPase activity and polyQ aggregation; altered response to nucleotide-triggered conformation change of the N domain [61, 62]; compromised ERAD and proteasome; accumulation of TDP-43; induced cell death [63, 64]; mitochondria defects [65]; rescued yeast cdc48 mutant [57]. |
| | L198W | N-D1 linker | IBMPFD | Enhanced binding to ubiquitylated substrates; impaired ERAD [59, 60, 63]. |
| | A232E | D1 domain | IBMPFD and ALS | Increased bindings to Ufd1, Npl4, p47, and ubiquitylated substrates; reduced bindings to CAV1, UBXD1 [58, 59]; normal hexmer; altered response to nucleotide-triggered conformation change of the N domain; altered conformation of the D2 ring [61, 62]; enhanced ATPase activity and polyQ aggregation; impaired ERAD, autophagy, and proteasome; accumulation of ubiquitin conjugates and TDP-43; induced cell death [63]; rescued yeast cdc48 mutant [57]. |
| | T262A | D1 domain | IBMPFD | Impaired degradation of ERAD substrates [55, 56, 63]. |
| | N387H | D1 domain | IBMPFD | Compromised ERAD; accumulation of ubiquitin containing inclusion [55, 63]. |
| | I27V, R95C, R97C, R97E, R155L, G157R, R159H, R159C | N domain | IBMPFD | |
| | R95H, I151V | N domain | ALS | |
| | I206F | N-D1 linker | IBMPFD | |
| | R191G | N-D1 linker | ALS | |
| | A439S, A439P | D1 domain | IBMPFD | |
| | D592N | D2 domain | ALS | |
|
|
