Novel compound heterozygous MRTFA gene variants cause multiple dysfunctions of neutrophils and autoinflammation.

Compound heterozygous mutations in the MRTFA gene have not been reported; the complete clinical phenotypic spectrum associated with MRTFA deficiency remains undefined. Whether such mutations can result in autoinflammatory manifestations is also yet to be determined. Comprehensive analyses were conducted on a patient with novel compound heterozygous MRTFA variants, encompassing clinical data collection, genetic validation, and functional studies. Functional assays included protein stability assessment, SRF transcriptional activity measurement, and neutrophil functional evaluation. Lymphocyte profiling was performed using flow cytometry. Transcriptomic alterations in neutrophils and PBMCs were examined through bulk RNA-sequencing. The patient presented with early-onset infections, rashes, and bloody stools, accompanied by neutropenia and thrombocytopenia. Whole-exome sequencing identified two novel heterozygous nonsense mutations in MRTFA (Q377X/C684X), which caused the absence of MKL1 protein expression and reduced cytoskeletal protein levels. Both mutants presented protein instability and impaired SRF transcriptional activation. F-actin content was reduced in various cell types from the patient. Neutrophils from the patient showed impaired F-actin polymerization, decreased migration ability, reduced ROS production, increased apoptosis, diminished NETs formation, and decreased MPO levels. Transcriptome profiling revealed neutrophil-specific downregulation of cytoskeletal genes with concomitant upregulation of antimicrobial peptide/inflammatory pathways, while PBMCs presented upregulated adhesion/migration-related genes. This study identifies the first reported case with compound heterozygous mutations in the MRTFA gene. The patient demonstrated a milder infectious phenotype but with marked neutrophil dysfunction and prominent autoinflammatory features. This study expands the disease spectrum of MKL1 deficiency and highlights the broader impacts of MKL1 deficiency on neutrophil function and immune regulation.