MRTFA – Immunodeficiency 66

MRTFA (also known as MKL1) is associated with autosomal recessive Immunodeficiency 66. Three affected individuals from two unrelated families harbor a homozygous loss-of-function frameshift in MRTFA, presenting in infancy with progressive severe pneumonia and poor wound healing (HP:0001058) (PMID:32128589). Affected siblings segregate the variant in a recessive pattern (2 affected relatives) with parents as asymptomatic carriers.

Functional characterization of MRTFA-deficient neutrophils reveals a marked actin polymerization defect, profoundly reduced motility and chemotaxis, and downregulation of multiple actin-related proteins by proteomic and transcriptomic analysis (PMID:32128589). Degranulation is enhanced under suboptimal activation, while reactive oxygen species generation and phagocytosis remain intact. Neutrophil adhesion persists but fails to achieve proper spreading and transendothelial migration, explaining the clinical susceptibility to bacterial infection. Nonhematopoietic fibroblasts show defective myofibroblast differentiation yet maintain migration and F-actin content via compensation by MKL2.

Mechanistically, MRTFA deficiency leads to loss of a key SRF coactivator required for cytoskeletal gene transcription, supporting a loss-of-function pathogenic mechanism. No studies to date dispute this association. Additional case series are needed to strengthen segregation data. Key Take-home: Genetic testing of MRTFA should be considered in infants with early-onset neutrophil motility defects and severe immunodeficiency, as hematopoietic stem cell transplantation may be curative.

References

• Blood • 2020 • MKL1 deficiency results in a severe neutrophil motility defect due to impaired actin polymerization. PMID:32128589

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