UNC93B1 GENE

The UNC93B1 gene (UNC93B1 stands for: Unc-93 Homolog B1, TLR Signaling Regulator) is a protein-coding gene located on chromosome 11q13.2.

The UNC93B1 gene encodes a protein that is involved in the innate and adaptive immune response by regulating toll-like receptor signaling. The encoded UNC93B1 protein transports nucleotide-recognizing Toll-like receptors from the endoplasmic reticulum to the endolysosome.UNC93B1 is critical for the transport and function of the nucleic acid-recognizing Toll-like receptors (TLRs) TLR3, TLR7, TLR8 and TLR9, which are essential for antiviral immunity. Overactive TLR7 signaling induced by self nucleic acid recognition has been associated with systemic lupus erythematosus (SLE).

The UNC93B1 variants (E92G and R336L) are associated with systemic lupus erythematosus. Patient cells carrying the UNC93B1 variants produced high levels of TNF-α and IL-6 after stimulation with TLR7/TLR8 agonists (but not with TLR3 or TLR9 agonists). E92G causes instability of the UNC93B1 protein leading to selective TLR7 hyperactivation with constitutive type I IFN signaling. This could have therapeutic potential in the targeted manipulation of TLR7 in SLE. Deficiency of the encoded protein has been associated with herpes simplex encephalitis.

AGS2568 This 10-year-old boy was born to unrelated parents of white European descent. Early in life, he had persistent, florid, chilblain-like lesions on his fingers and toes with occasional ulcers, sometimes involving his ears. Reportedly, his mother, maternal aunt and maternal grandfather had similar lesions that appeared in the first decade of life. Extensive autoantibody screening was negative. IFN signaling was not investigated. He was found to carry a heterozygous c.989T>G/p.(Leu330Arg) substitution in UNC93B1 present on 8/1,552,226 alleles on gnomAD v4. DNA from other family members was not available.

AGS2650 This 10-year-old female was born to unrelated parents of Indian descent. The pregnancy was normal and she was delivered at term weighing 2.2 kg. She was doing well until she developed fever and vomiting at the age of 18 months and was diagnosed with severe anemia (hemoglobin level of 3.4 g/dL). She was diagnosed with autoimmune hemolytic anemia, which required multiple transfusions, steroids and azathioprine. Antinuclear antibody and double-stranded DNA antibody titers were positive (1:100 dilution) and complement was low (C3 47.6 mg/dl, normal range 90-180; C4 <6.4 mg/dl, normal range 10-40), leading to the diagnosis of SLE. Her development is normal. At the age of 7.5 years, she weighed 20 kg (10th percentile) and was 110 cm tall (2 SD below the mean). IFN signaling was not assessed. She was found to be homozygous for a c.951C>G/p.(Ile317- Met) substitution in UNC93B1, which was not present in gnomAD. Parental DNA was not available.

AGS2672 This 5-year-old female was born to unrelated parents of white European ancestry. At 4 months of age, she developed vasculitic lesions on both palms and soles and sometimes ulcers in the mouth. Autoantibodies were consistently negative. Inflammatory markers were slightly but persistently elevated. A skin biopsy at the age of 2 years showed non-specific inflammatory changes. Her disease was refractory to treatment with steroids and methotrexate, leading to treatment with baricitinib, which showed some positive results. Blood IFN signaling was elevated in the six tests over a period of >3 years between the ages of 6 and 9 years (IFN levels between 11.41 and 25.92 - normal <2.758). She was found to carry a heterozygous c.1398A>C/p.(Arg466Ser) mutation in UNC93B1, which was not present in gnomAD. Her mother does not carry the same variant. The paternal DNA was not available

1. David C et al. (2024) Gain-of-function human UNC93B1 variants cause systemic lupus erythematosus and chilblain lupus. J Exp Med 221:e20232066.
2. Menzel K et al. (2024) Monogenic lupus - from gene to targeted therapy. Mol Cell Pediatr 11:8.
3. Wolf C et al. (2024) UNC93B1 variants underlie TLR7-dependent autoimmunity. Sci Immunol 9:eadi9769.