Presenter of 1 Presentation
HETEROZYGOUS LOSS OF MAP4K1 ENCODING FOR HEMATOPOIETIC PROGENITOR KINASE 1 (HPK1), A NEGATIVE REGULATOR OF TCR SIGNALING, CAN LEAD TO IMMUNE DYSREGULATION
Abstract
Background and Aims
MAP4K1 encodes for hematopoietic progenitor kinase 1 (HPK1) which negatively regulates TCR and BCR signaling in lymphocytes. MAP4K1-knockout mice show increased T cell proliferation, secretion of proinflammatory cytokines, and susceptibility to autoimmunity. In humans, decreased levels of HPK1 have been found in patients with psoriatic arthritis and systemic lupus erythematosus but evidence of direct causality between HPK1 and human immune disorders is lacking.
Methods
We employed genotyping and exome sequencing to identify the underlying genetic defect in a multigenerational pedigree with nine affected individuals exhibiting dominantly inherited autoimmunity/inflammation. RT-PCR, RNA-sequencing, flow cytometry and western blotting were utilized for patient characterization and analysis of candidate variant effects.
Results
Symptoms in the studied pedigree included prolonged fevers of unknown cause and recurrent joint inflammation, as well as untypical Still's disease, Kawasaki disease and urticaria in one patient, and HLH in another. Genetic linkage analysis indicated highest probability of disease variant at the genomic location chr19:35079781-45414451 (hg19, maximum LOD-score 2.067), where exome sequencing identified a novel splice-site variant in MAP4K1 (NM_007181:exon23:c.1778+2T>G). RT-PCR and western blotting confirmed altered splicing of MAP4K1 and loss of HPK1 protein production from the variant allele in patient-derived PBMCs. The patients had normal immune cell composition but exhibited increased levels of proinflammatory cytokines in their plasma. Gene Set Enrichment Analysis of RNA-sequencing data indicated increased expression of genes involved in NF-κB-mediated TNFα signaling and inflammatory responses in patient PBMCs. Further functional tests are pending.
Conclusions
Heterozygous loss of MAP4K1/HPK1 is a possible novel cause of autoinflammation and autoimmunity.