Proteasome-Associated Autoinflammatory Syndrome 2

A number sign (#) is used with this entry because of evidence that proteasome-associated autoinflammatory syndrome-2 (PRAAS2) is caused by heterozygous mutation in the POMP gene (613386) on chromosome 13q12.

Description

Proteasome-associated autoinflammatory syndrome-2 is an autosomal dominant disorder with onset in early infancy. Affected individuals develop severe inflammatory neutrophilic dermatitis, autoimmunity, and variable immunodeficiency (summary by Poli et al., 2018).

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

Clinical Features

Megarbane et al. (2002) reported a boy, born of unrelated Palestinian parents, who presented soon after birth with recurrent febrile attacks associated with painful joints and periorbital edema, followed by weakness. He also had delayed development and began to walk at 4 years of age, but had normal cognition at age 10. He had subcutaneous nodules, which showed leukocytoclastic vasculitis and chronic lymphadenitis on biopsy. Additional features included short stature, poor overall growth, brachydactyly, large interphalangeal articulations, clinodactyly, flat feet, and dysmorphic features, including large nasal bridge, everted lower lip, and bifid uvula. Laboratory studies showed increased C-reactive protein. The findings suggested an autoinflammatory syndrome.

Poli et al. (2018) reported 2 unrelated boys with a severe neonatal-onset inflammatory disease. The patients presented in the second week of life with diffuse papuloerythematous skin lesions on the face, trunk, and extremities, which progressed to necrotizing lesions and scarring. Skin biopsy showed neutrophil infiltration consistent with neutrophilic dermatosis. Skin biopsy from 1 patient also showed thrombotic vasculopathy with vascular fibrinoid necrosis. The patients also had recurrent viral and bacterial infections, particularly of the respiratory tract, and episodic fever. One patient had disseminated mycobacterial disease and the other had severe recurrent viral infections and Pneumocystis jiroveci. Immunologic workup showed high total T cell numbers with low CD8+ T cells and high CD4+ T cells, most of which were skewed to a naive phenotype. Functional studies showed impaired cytokine production in T cells. B-cell counts were initially low, but some B cells were later detected and were skewed to a memory phenotype with increased production of IgA, IgE, and IgG. Both patients had high levels of circulating autoantibodies, including anti-nuclear antibodies and those against beta-2 glycoprotein 1 (B2GP1, APOH; 138700). The findings were consistent with increased autoantibody production, and one of the patients showed a partial response to rituximab. Additional features included cyclic thrombocytopenia in both patients, and seizures in 1 patient. Overall, the findings suggested a complex phenotype with combined immunodeficiency, autoimmunity, and autoinflammation. The patients were referred for hematopoietic stem cell transplantation.

Molecular Genetics

In the patient reported by Megarbane et al. (2002), Brehm et al. (2015) identified a heterozygous frameshift mutation in the POMP gene (613386.0002). The mutation, which was found by whole-exome sequencing and by screening of proteasome candidate genes, was confirmed by Sanger sequencing. Parental samples were not available for segregation analysis. Patient cells were not available for study, but siRNA-mediated knockdown of the POMP gene resulted in reduced proteasome formation with accumulation of precursors and reduced overall proteasome activity.

In 2 unrelated boys with PRAAS2, Poli et al. (2018) identified de novo heterozygous frameshift mutations in the POMP gene (613386.0003 and 613386.0004). The mutations were found by whole-exome sequencing and confirmed by Sanger sequencing. Functional studies showed that the variants escaped nonsense-mediated mRNA decay and produced truncated proteins. Cell lines derived from both individuals showed impaired assembly of the proteasome, with decreased levels of 20S proteasome, decreased incorporation of proteasome subunits, and increased proteasomal precursor complexes. There was also evidence of aggregation of ubiquitin-modified proteins and activation of the unfolded protein response, indicating ER stress. Both hematopoietic and nonhematopoietic cells from both individuals also showed a 4-fold higher expression of type I interferon-inducible genes compared to controls. Overexpression of the mutations with wildtype POMP in HEK293 cells resulted in similar abnormalities. The findings were consistent with a toxic gain-of-function effect rather than haploinsufficiency.