2. Academic Validation
  3. Genetic variants in UNC93B1 predispose to childhood-onset systemic lupus erythematosus

Genetic variants in UNC93B1 predispose to childhood-onset systemic lupus erythematosus

  • Nat Immunol. 2024 Jun;25(6):969-980. doi: 10.1038/s41590-024-01846-5.
Mahmoud Al-Azab # 1 2,  Elina Idiiatullina # 1 3,  Ziyang Liu 1,  Meng Lin 1,  Katja Hrovat-Schaale 4 5,  Huifang Xian 1,  Jianheng Zhu 1,  Mandy Yang 6,  Bingtai Lu 1,  Zhiyao Zhao 1 7,  Yiyi Liu 1,  Jingjie Chang 1,  Xiaotian Li 1,  Caiqin Guo 1,  Yunfeng Liu 8,  Qi Wu 1 9,  Jiazhang Chen 1,  Chaoting Lan 1,  Ping Zeng 1,  Jun Cui 10,  Xia Gao 1,  Wenhao Zhou 1,  Yan Zhang 1,  Yuxia Zhang 11,  Seth L Masters 12 13 14 15 16
Affiliations

Affiliations

  • 1 Department of Immunology, Guangzhou Institute of Paediatrics, Guangzhou Women and Children's Medical Centre, and State Key Laboratory of Respiratory Diseases, Guangzhou Medical University, Guangzhou, China.
  • 2 Department of Medical Microbiology, Faculty of Medicine, University of Science and Technology, Aden, Yemen.
  • 3 Department of Therapy and Nursing, Bashkir State Medical University, Ufa, Russia.
  • 4 Inflammation Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
  • 5 Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia.
  • 6 State Key Laboratory of Respiratory Diseases, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China.
  • 7 Center for Mitochondrial Genetics and Health, Greater Bay Area Institute of Precision Medicine (Guangzhou), Guangzhou, China.
  • 8 Clinical Laboratory, Guangzhou Women and Children's Medical Centre, Guangzhou Medical University, Guangdong, China.
  • 9 National Children Medical Center, Department of Clinical Immunology, Children's Hospital of Fudan University, Shanghai, China.
  • 10 School of Life Sciences, Sun Yat-sen University, Guangzhou, China.
  • 11 Department of Immunology, Guangzhou Institute of Paediatrics, Guangzhou Women and Children's Medical Centre, and State Key Laboratory of Respiratory Diseases, Guangzhou Medical University, Guangzhou, China. yuxia.zhang@gwcmc.org.
  • 12 Department of Immunology, Guangzhou Institute of Paediatrics, Guangzhou Women and Children's Medical Centre, and State Key Laboratory of Respiratory Diseases, Guangzhou Medical University, Guangzhou, China. seth.masters@hudson.org.au.
  • 13 Inflammation Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia. seth.masters@hudson.org.au.
  • 14 Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia. seth.masters@hudson.org.au.
  • 15 Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria, Australia. seth.masters@hudson.org.au.
  • 16 Department of Molecular and Translational Science, Monash University, Clayton, Victoria, Australia. seth.masters@hudson.org.au.
  • # Contributed equally.
PMID: 38831104 DOI: 10.1038/s41590-024-01846-5
Abstract

Rare genetic variants in Toll-like Receptor 7 (TLR7) are known to cause lupus in humans and mice. UNC93B1 is a transmembrane protein that regulates TLR7 localization into endosomes. In the present study, we identify two new variants in UNC93B1 (T314A, located proximally to the TLR7 transmembrane domain, and V117L) in a cohort of east Asian patients with childhood-onset systemic lupus erythematosus. The V117L variant was associated with increased expression of type I interferons and NF-κB-dependent cytokines in patient plasma and immortalized B cells. THP-1 cells expressing the variant UNC93B1 alleles exhibited exaggerated responses to stimulation of TLR7/-8, but not TLR3 or TLR9, which could be inhibited by targeting the downstream signaling molecules, IRAK1/-4. Heterozygous mice expressing the orthologous Unc93b1V117L variant developed a spontaneous lupus-like disease that was more severe in homozygotes and again hyperresponsive to TLR7 stimulation. Together, this work formally identifies genetic variants in UNC93B1 that can predispose to childhood-onset systemic lupus erythematosus.

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