Table 1.
Current genetic and clinical spectrum of monogenic proteasome-associated inflammatory diseases
| Gene | PSMB87,10,14,15,16 | POMP12,17 | PSMB48,18 | PSMG29 | PSMB1011,19 | PSMB120 | PSMD1221,22,23,24 | PSMC3,25 | PSMC326, | PSMB913 |
|---|---|---|---|---|---|---|---|---|---|---|
| Disease | PRAAS1 (MIM: 256040 | PRAAS2 (MIM: 618048) | PRAAS3 (MIM: 617591) | PRAAS4 (MIM: 619183) | PRAAS5 (MIM: 619175) | NDD (MIM: 620038) | Stankiewicz–Isidor syndrome (MIM: 617516) | NDD | DCIDP (MIM: 619354) | PRAAS-ID |
| Mutational mechanism | AR LoF | AD LoF DN | AR LoF | AR LoF | AR LoF | AR LoF | AD LoF HI | AD LoF | AR LoF | De novo LoF DN |
| Encoded protein | Subunit β5i | proteasome maturation protein | subunit β7 | assembly chaperone 2 | subunit β2i | subunit β6 | 19S/26S subunit, non-ATPase 12 | 19S/26S subunit, ATPase 3 | 19S/26S subunit, ATPase 3 | subunit β1i |
| Proteasome defect | 20S, 26S IP defect | 20S, 26S IP + SP defect | 20S, 26S IP + SP defect | 20S, 26S IP + SP defect | 20S, 26S IP defect | 20S, 26S SP defect | 20S IP + SP defect | 20S, 26S SP + IP defect | decreased ubiquitylation, proteotoxic stress | 20S IP defect |
| Clinical findings | ||||||||||
| Periodic fever | + | + | + | + | + | – | – | – | – | + |
| Skin rash | + | + | + | + | + | – | + | – | – | + |
| Myositis/muscle dystrophy | + | – | + | + | – | N/A | N/A | – | – | + |
| Arthritis | + | + | + | – | – | – | – | – | – | – |
| Liver dysfunction | + | N/A | + | N/A | N/A | N/A | N/A | N/A | N/A | + |
| Infections | +/− | + | + | – | N/A | – | – | – | – | + |
| Pneumonia | + | + | + | – | – | – | – | – | – | + |
| Splenomegaly | + | – | + | + | + | – | – | – | – | +/− |
| Lipodystrophy | + | + | + | + | N/A | – | – | – | – | – |
| Basal ganglia calcification | +/− | – | – | + | N/A | N/A | – | N/A | N/A | + |
| IFN-I signature | + | ++ | + | + | + | N/A | + | + | N/A | =/+ |
| Viremia | N/A | N/A | – | – | N/A | N/A | – | – | – | + |
| Congenital malformations (incl. facial dysmorphism) | + | + | N/A | N/A | + | ++ (short stature, deafness) | +++ (deafness) | +++ (deafness) | +++ (cataract, deafness) | N/A |
| Neurological abnormalities | + | + | N/A | + | N/A | +++ (IDD) | +++ (IDD, autism) | +++ (IDD) | +++ (IDD, PNP) | – |
| Laboratory evaluation | ||||||||||
| Elevated inflammatory markers | + | + | + | + | + | N/A | + | N/A | N/A | + |
| Microcytic anemia | + | N/A | +/− | – | + | N/A | N/A | N/A | N/A | N/A |
| Thrombocytopenia | =/↑ | + | + | + | =/↑ | N/A | N/A | N/A | N/A | + |
| T cell | N/A | CD4 ↑, CD8 ↓, CD4/CD8 ratio ↑, naive T cell phenotype | low CD8, CD4/CD8 ratio ↑ | N/A | N/A | N/A | variable | N/A | N/A | variable |
| B cell | N/A | ↓ | variable | N/A | N/A | N/A | =/↑ | N/A | N/A | =/↓ |
| Serum Ig | ↑ | Dysgamma-globulinemia | =/↑ | N/A | normal | N/A | N/A | N/A | N/A | IgG ↓ |
| Auto-antibodies | variable | + | + | + | N/A | N/A | N/A | N/A | N/A | – |
AD, autosomal-dominant; AR, autosomal-recessive; DCIDP, deafness, cataract, impaired intellectual development, and polyneuropathy; DN, dominant-negative; HI, haploinsufficiency; IDD, intellectual and developmental disability; IFN-I, type-I interferon; LoF, loss-of-function; NDD, neurodevelopmental disorders; PNP, polyneuropathy.