NIH Research Festival
Human primary immunodeficiency diseases (PID) are a large group of disorders affecting the development, function and regulation of the immune system. Although 320 single-gene defects are known to cause PID, patients with unknown etiology often undergo next generation sequencing in order to discover novel genetic variants that underlie their disease. One such case was a seven year-old male from a consanguineous Turkish family that presented with recurrent respiratory infections, otitis media and hepatosplenomegaly at three months of age. A computed tomography scan showed infiltrates, as well as two large cavitary lesions in the lungs of the patient. The patient also exhibited highly elevated levels of IgE in the serum. Collectively, the clinical phenotype largely mirrored that of Hyper-IgE syndrome; however, the patient tested negative for variants in STAT3 and DOCK8, mutations in which are known to cause this disease. Through whole exome sequencing, we identified a homozygous frameshift mutation (c.1887_1888delCT; p.Cys630LeufsTer19) in RHBDF2 (iRhom2), which resulted in significantly reduced RHBDF2 mRNA in the patient likely due to nonsense-mediated decay. iRhom2 is an enzymatically inactive member of the rhomboid superfamily that is highly expressed in the immune system and plays an important role in protein trafficking and stabilization. Specifically, iRhom2 has been shown to interact and traffic TNF-converting enzyme (TACE or ADAM17) from the endoplasmic reticulum to the plasma membrane. TACE is an intramembrane metalloprotease that cleaves and releases a large number of substrates on the cell surface, including TNF and members of the epidermal growth factor family. Patient monocytes and T cells exhibited significantly higher levels of TNF on the cell surface and reduced soluble TNF in cell culture supernatants upon stimulation with LPS or anti-CD3 antibody, respectively. Further, a western blot of TACE from patient T cell lysates showed accumulation of pro-TACE and very little processed TACE, consistent with a defect in TACE trafficking and maturation. Overall, we have identified a novel mutation in RHBDF2 in a patient with PID that results in defects in TACE maturation/activity. Future studies aim to identify new client proteins of iRhom2 in the immune system that could help further explain the clinical phenotype of this patient with immunodeficiency.
Scientific Focus Area: Genetics and Genomics
This page was last updated on Friday, March 26, 2021