Background and Aims

LUBAC is a heterotrimeric complex composed of SHARPIN, HOIL-1 and HOIP. LUBAC is involved in NFkB pathway activation and cell survival. Patients with complete HOIL-1 or HOIP deficiency suffer from inflammatory manifestations and immune deficiency. We identified by whole exome sequencing a heterozygous SHARPIN mutation in a patient with autoimmunity, inflammatory manifestations and primary antibody deficiency. We aimed to study the link between this mutation and the disease of the patient.

Methods

To study the mutation’s impact on the production, stability and function of the protein we transiently transfected HEK293T cells and complemented SHARPIN^-/- Jurkat cells by lentiviral infection. We also evaluated LUBAC-dependent functions in patient’s PBMCs and SV40-transformed fibroblasts.

Results

The mutation led to a premature STOP codon and the diminished production of a non-functional truncated protein.

Patient’s cells presented a decreased TNFα and IL-1β-induced canonical NFkB activation and an excess of TNFα -induced cell death.

Patient’s monocytes secreted higher amount of IL6 after IL-1β stimulation than healthy controls.

Anti-cytokine biotherapies (anti-TNFα and IL1receptor antagonist) led to a partial improvement of the patient’s inflammatory manifestations.

Conclusions

We describe the first dominant hypomorphic SHARPIN mutation in a patient with autoimmunity, inflammatory manifestations and primary immune deficiency.

Clinical manifestations and experimental data are similar, although milder, to those described in HOIL-1 or HOIP deficient patients. Study of such rare inborn errors of immunity contribute to a better understanding of inflammatory and autoimmune diseases and lead to identification of new therapeutic targets.