Loss of Function Mutation in ELF4 Causes Autoinflammatory and Immunodeficiency Disease in Human

  • J Clin Immunol. 2022 May;42(4):798-810. doi: 10.1007/s10875-022-01243-3.
Gan Sun  1  2  3 ,  Luyao Qiu  1  2  3 ,  Lang Yu  1  2  3 ,  Yunfei An  1  2  3  4 ,  Yuan Ding  1  2  3 ,  Lina Zhou  1  2  3 ,  Junfeng Wu  1  2  3  4 ,  Xi Yang  1  2  3  4 ,  Zhiyong Zhang  1  2  3  4 ,  Xuemei Tang  1  2  3  4 ,  Huawei Xia  5 ,  Lili Cao  5 ,  Fuping You  5 ,  Xiaodong Zhao  6  7  8  9 ,  Hongqiang Du  10  11  12  13
Affiliations
  • 1. National Clinical Research Center for Child Health and Disorders (Chongqing), Children's Hospital of Chongqing Medical University, Chongqing, China.
  • 2. Ministry of Education Key Laboratory of Child Development and Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China.
  • 3. Chongqing Key Laboratory of Child Infection and Immunity, Children's Hospital of Chongqing Medical University, Chongqing, China.
  • 4. Department of Rheumatology & Immunology, Children's Hospital of Chongqing Medical University, Chongqing, China.
  • 5. Beijing Key Laboratory of Tumor Systems Biology, Department of Immunology, School of Basic Medical Sciences, Institute of Systems Biomedicine, Peking University Health Science Center, Beijing, 100000, China.
  • 6. National Clinical Research Center for Child Health and Disorders (Chongqing), Children's Hospital of Chongqing Medical University, Chongqing, China. [email protected].
  • 7. Ministry of Education Key Laboratory of Child Development and Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China. [email protected].
  • 8. Chongqing Key Laboratory of Child Infection and Immunity, Children's Hospital of Chongqing Medical University, Chongqing, China. [email protected].
  • 9. The Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400014, China. [email protected].
  • 10. National Clinical Research Center for Child Health and Disorders (Chongqing), Children's Hospital of Chongqing Medical University, Chongqing, China. [email protected].
  • 11. Ministry of Education Key Laboratory of Child Development and Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China. [email protected].
  • 12. Chongqing Key Laboratory of Child Infection and Immunity, Children's Hospital of Chongqing Medical University, Chongqing, China. [email protected].
  • 13. Department of Rheumatology & Immunology, Children's Hospital of Chongqing Medical University, Chongqing, China. [email protected].
PMID: 35266071 DOI: 10.1007/s10875-022-01243-3
Abstract

Monogenic autoinflammatory diseases (mAIDs) are a heterogeneous group of diseases affecting primarily innate immunity, with various genetic causes. Genetic diagnosis of mAIDs can assist in the patient's management and therapy. However, a large number of sporadic and familial cases remain genetically uncharacterized. Deficiency in ELF4, X-linked (DEX) is recently identified as a novel mAID. Here, we described a pediatric patient suffering from recurrent viral and Bacterial respiratory Infection, refractory oral ulcer, constipation, and arthritis. Whole-exome Sequencing found a hemizygous variant in ELF4 (chrX:129205133 A > G, c.691 T > C, p.W231R). Using cells from patient and point mutation mice, we showed mutant cells failed to restrict viral replication effectively and produced more pro-inflammatory cytokines. RNA-seq identified several potential critical Antiviral and anti-inflammation genes with decreased expression, and ChIP-qPCR assay suggested mutant ELF4 failed to bind to the promoters of these genes. Thus, we presented the second report of DEX.

Keywords
Autoinflammatory disease; ELF4; Immunodeficiency; Inborn errors of immunity; Loss of function.