Immune deficiencies, infection, and systemic immune disorders
Haploinsufficiency of TNFAIP3 (A20) by germline mutation is involved in autoimmune lymphoproliferative syndrome

https://doi.org/10.1016/j.jaci.2016.09.038Get rights and content

Background

Autoimmune diseases in children are rare and can be difficult to diagnose. Autoimmune lymphoproliferative syndrome (ALPS) is a well-characterized pediatric autoimmune disease caused by mutations in genes associated with the FAS-dependent apoptosis pathway. In addition, various genetic alterations are associated with the ALPS-like phenotype.

Objective

The aim of the present study was to elucidate the genetic cause of the ALPS-like phenotype.

Methods

Candidate genes associated with the ALPS-like phenotype were screened by using whole-exome sequencing. The functional effect of the identified mutations was examined by analyzing the activity of related signaling pathways.

Results

A de novo heterozygous frameshift mutation of TNF-α–induced protein 3 (TNFAIP3, A20), a negative regulator of the nuclear factor κB pathway, was identified in one of the patients exhibiting the ALPS-like phenotype. Increased activity of the nuclear factor κB pathway was associated with haploinsufficiency of TNFAIP3 (A20).

Conclusion

Haploinsufficiency of TNFAIP3 (A20) by a germline heterozygous mutation leads to the ALPS phenotype.

Section snippets

Cell culture

Control and patient-derived PBMCs were cultured as activated T cells. PBMCs were stimulated with anti-CD2, anti-CD3, and anti-CD28 beads, according to the manufacturer's protocol (Miltenyi Biotec, Gladbach, Germany), and expanded with ALyS505N-0 Medium (Cell Science & Technology Institute, Miyagi, Japan) supplemented with 10% FBS and 50 g/mL recombinant human IL-2 (PeproTech, Rocky Hill, NJ).

Genome analysis

Genomic analysis was performed after obtaining informed consent from each patient. The genetic analysis

Case description

A 7-month-old Japanese boy had a fever and was found to have increased levels of C-reactive protein. The patient was treated with antibiotics, which had no significant effect. After spontaneous resolution of the fever, liver dysfunction was transiently observed for 2 months. The patient presented to the hospital at 1 year of age with fever, cervical lymph node swelling, and skin rash. Bilateral cervical lymphadenopathy and hepatosplenomegaly were noted (Fig 1, A and B). Because the fever

Discussion

TNFAIP3 (A20) heterozygous knockout mice appear normal without evidence of pathology; however, TNFAIP3 (A20) homozygous knockout mice show severe inflammation, are hypersensitive to both LPS and TNF, and die prematurely.22 The human TNFAIP3 (A20) locus and its polymorphisms are associated with certain conditions, such as Crohn disease, rheumatoid arthritis, systemic lupus erythematosus, psoriasis, and type 1 diabetes.23 These findings further illustrate the importance of TNFAIP3 (A20) in the

References (27)

Cited by (0)

Supported by a Grant-in-Aid for Research on Measures for Intractable Diseases from the Japan Agency for Medical Research and Development (AMED), 27280301 and 26070201.

Disclosure of potential conflict of interest: M. Takagi and S. Ogawa receive research support from a Grant-in-Aid for Research on Measures for Intractable Diseases from the Japan Agency for Medical Research and Development. The rest of the authors declare that they have no relevant conflicts of interest.

These authors contributed equally to this work.

View full text