A number sign (#) is used with this entry because of evidence that proteasome-associated autoinflammatory syndrome-3 (PRAAS3) is caused by homozygous mutation in the PSMB4 gene (602177) on chromosome 1q21. One such patient has been reported.

One unrelated family with a similar phenotype was found to have a digenic form of PRAAS3 due to a heterozygous mutation in the PSMB4 gene and a heterozygous mutation in the PSMB9 gene (177045) on chromosome 6p21.

Proteasome-associated autoinflammatory syndrome-3 is an autosomal recessive syndrome with onset in early infancy. Affected individuals present with nodular dermatitis, recurrent fever, myositis, panniculitis-induced lipodystrophy, lymphadenopathy, and dysregulation of the immune response, particularly associated with abnormal type I interferon-induced gene expression patterns. Additional features are highly variable, but may include joint contractures, hepatosplenomegaly, anemia, thrombocytopenia, recurrent infections, autoantibodies, and hypergammaglobulinemia. Some patients may have intracranial calcifications (summary by Brehm et al., 2015).

For a discussion of genetic heterogeneity of PRAAS, see PRAAS1 (256040).

Liu et al. (2012) reported a 5.5-year-old Caucasian boy of American descent (patient 6) with onset of an autoinflammatory disease in the first 2 weeks of life. He presented with a rash, periorbital erythema with violaceous eyelids, and swelling of the foot. He had recurrent fevers associated with increased acute-phase reactants (erythrocyte sedimentation rate and C-reactive protein), lymphadenopathy, finger swelling, annular plaques, hepatosplenomegaly, and failure to thrive with poor overall growth. Additional features included arthritis, prominent abdomen with lipodystrophy, recurrent otitis and sinusitis, and bronchiolitis obliterans organizing pneumonia (BOOP) of the lungs, consistent with inflammation. Laboratory studies showed hypochromic anemia, intermittently elevated liver function tests, and mildly increased triglycerides. He was treated with multiple antiinflammatory medications, including steroids and methotrexate, without success. Brehm et al. (2015) reported follow-up of this patient (patient 1) at age 8 years. He was also noted to have myositis, joint contractures, hypergammaglobulinemia, antinuclear autoantibodies, thrombocytopenia, lymphopenia, and metabolic syndrome.

Digenic Inheritance

Brehm et al. (2015) reported 2 sibs of Jamaican descent (family 4) with digenic PRAAS (see MOLECULAR GENETICS). The patients presented in the first week of life with skin lesions, fever, and swallowing difficulties. They had annular plaques, violaceous eyelids, conjunctivitis, keratitis, hyperpigmented macules, and scarring. Additional features included poor overall growth, lymphadenopathy, myositis, arthritis/arthralgias, joint contractures, and lipodystrophy. Most had recurrent infections. Laboratory studies showed elevated acute phase reactants, microcytic anemia, thrombocytopenia, lymphopenia, hypercholesterolemia, and variable hypergammaglobulinemia. One patient had autoantibodies. More variable features included metabolic syndrome and peripheral calcinosis.

The transmission pattern of PRAAS3 in a family (family 1) reported by Brehm et al. (2015) was consistent with autosomal recessive inheritance.

The transmission pattern of PRAAS3 in another family (family 4) reported by Brehm et al. (2015) was consistent with digenic inheritance, with heterozygous mutations in the PSMB4 and PSMB9 (177045) genes.

In an 8-year-old Caucasian boy of American descent (patient 1) with PRAAS3, Brehm et al. (2015) identified compound heterozygous mutations in the PSMB4 gene (602177.0001 and 602177.0002). The mutations, which were found by a combination of whole-exome sequencing and sequencing of proteasome candidate genes and confirmed by Sanger sequencing, segregated with the disorder in the families. Detailed functional studies, including in vitro studies of patient cells, expression of the mutations into HeLa cells, and siRNA-mediated knockdown of the proteasomal genes, demonstrated that the mutations resulted in variable defects in proteasome 20S and 26S assembly and maturation, with accumulation of proteasome precursor complexes, as well as impaired proteolytic activity. The defects were associated with induction of a type I interferon response with strong expression of IFN-inducible genes and an increase in the secretion of chemokines and cytokines. Patient skin biopsies showed increased ubiquitin-positive keratinocytes and impaired proteasomal assembly due to impaired incorporation of subunits. Brehm et al. (2015) concluded that mutations in proteasomal subunit genes adversely affect proteasomal function, leading to cell stress and the triggering of a type I IFN gene response, causing a vicious cycle of uncontrolled inflammation in both hematopoietic and nonhematopoietic cells.

Digenic Inheritance

Brehm et al. (2015) reported 2 sibs of Jamaican descent (family 4) with digenic PRAAS. A combination of whole-exome sequencing and sequencing of proteasome candidate genes showed that the patients had a heterozygous mutation in the PSMB4 gene (602177.0003) on 1 allele and a heterozygous mutation in the PSMB9 gene (177045.0001) on the other allele. The mutations were confirmed by Sanger sequencing and segregated with the disorder in the family.