In 3 affected members from 2 unrelated families with proteasome-associated autoinflammatory syndrome-1 (PRAAS1; 256040), Agarwal et al. (2010) identified a homozygous 224C-T transition in exon 2 of the PSMB8 gene, resulting in a thr75-to-met (T75M) substitution in a highly conserved residue. The mutation was not found in 275 controls but was present in heterozygosity in available parents and unaffected sibs. The patients had previously been reported by Garg et al. (2010) and were of Portuguese and Mexican origin, respectively. The parents of the Portuguese patients were consanguineous, whereas consanguinity was suspected in the parents of the Mexican patients. Haplotype analysis indicated identity by descent, but the mutation appeared to be ancient. Molecular dynamics simulation indicated that the mutation relaxed the protein structure by 1.2 angstrom, and may affect the proteolytic processing of peptides. Studies of patient lymphocytes showed that the mutant protein had markedly decreased chymotrypsin-like activity compared to wildtype, consistent with a decrease in proteasomal activity and loss of function. Laboratory studies of the 2 Mexican sibs performed by Agarwal et al. (2010) showed that both had significantly increased levels of serum IL6 (147620) and gamma-interferon (IFNG; 147570), and 1 had increased IL8 (146930). Other cytokines were not elevated, suggesting a particular biomarker signature. The disorder is characterized by childhood onset of joint stiffness and severe contractures of the hands and feet, erythematous skin lesions with subsequent development of severe lipodystrophy, and laboratory evidence of immune dysregulation. Accompanying features include muscle weakness and atrophy, hepatosplenomegaly, and microcytic anemia. The findings indicated that dysfunction of the immunoproteasome can result in an autoinflammatory disease.
Liu et al. (2012) identified a homozygous T75M mutation in 4 unrelated patients (patients 1, 2, 5, and 8) with PRAAS1. The deceased sister of patient 2 (patient 3) was similarly affected and assumed to carry the same homozygous mutation. Patients 1, 2, 3, and 4 had previously been reported by Torrelo et al. (2010). The clinical features were similar to those reported by Garg et al. (2010). Patients 3, 4, and 8 reported by Liu et al. (2012) were of Hispanic origin and patients 1 and 2 were of Spanish origin. However, only 2 patients shared the same haplotype, suggesting that T75 is a mutational hotspot. Two additional patients (patients 7 and 9) reported by Liu et al. (2012) were heterozygous for the T75M mutation, but a second mutation was not detected.
In the 2 patients (patients 7 and 9) with PRAAS1 reported by Liu et al. (2012) who were heterozygous for the T75M mutation, Brehm et al. (2015) identified heterozygous mutations in the PSMA3 gene (176843.0001 and 176843.0002) on the other allele, indicating digenic inheritance. Brehm et al. (2015) referred to the patients as patient 2 (American/Caucasian origin) and patient 3 (Spanish origin).
