New variants of the MRTFA gene broaden the spectrum of actinopathy with low white blood cell counts and inflammation

Article title: Des nouveaux variants de MRTFA expandent le phénotype de cette actinopathie avec neutropénie et manifestations autoinflammatoires

First author: Wendao Li

Journal: Pediatric Allergy and Immunology

Link to the article: https://pubmed.ncbi.nlm.nih.gov/40808667/

Author of the abstract: Philippe Mertz

Three key points to remember:

1. MKL1 deficiency was known to cause major disruption of the actin cytoskeleton and severe primary immunodeficiency with phagocyte defects.

2. The authors report here the first case of composite heterozygous variants in MRTFA, broadening the known phenotypic spectrum with major autoinflammatory manifestations and abnormalities in neutrophil number and function at the forefront.

3. As illustrated here, the full phenotype of actinopathies remains to be discovered, highlighting the importance of accurate diagnosis and in-depth functional investigations.

The MRTFA gene encodes the Megakaryoblastic Leukemia 1 (MKL1) protein, a regulator of the SRF transcription factor that induces the transcription of genes involved in actin cytoskeleton homeostasis, cell migration, and adhesion in multiple cell types. Normally, G-actin polymerization releases MKL1, allowing it to enter the nucleus to coactivate SRF-targeted genes.

The MKL1 defect was initially described in 2015 in three patients who presented with a phenotype of actinopathy with combined immunodeficiency, including a defect in the number and function of phagocytes. These earlier cases, from consanguineous families, had homozygous variants leading to the complete absence of the MKL1 protein. The classic clinical picture included increased susceptibility to severe bacterial infections, poor wound healing, and thrombocytopenia.

This article reports the fourth patient with MKL1 deficiency and the first reported case associated with composite heterozygous variants in the MRTFA gene (NM_020831; p.Q377X/p.C684X). These two variants are located in critical domains of the MKL1 protein, resulting in the complete absence of the protein in PBMCs and neutrophils, and therefore of its function as a regulator of actin metabolism gene transcription factors.

The patient, aged 3 years and from a non-consanguineous family, presented her first symptoms at the age of 2 months. She suffered from early infections, intermittent neutropenia, and thrombocytopenia, with a nadir of 55 G/L. Unlike the cases initially described in the literature, the infections observed in this patient were relatively less severe. However, she had marked autoinflammatory manifestations, characterized by recurrent febrile episodes associated with multiple erythematous and papular skin lesions affecting the face and limbs, as well as swelling of the hands and feet. She also had intermittent bloody diarrhea, rectal ulcers, colitis, and colonic lymphoid follicular hyperplasia, as confirmed by endoscopy.

Figure extraite de l’article

The authors conducted several functional explorations to understand the impact of these variants:

The absence of MKL1 caused marked dysfunction of the actin cytoskeleton, characteristic of actinopathies. A significant reduction in filamentous actin (F-actin) content was observed in neutrophils, monocytes, and, to a lesser extent, T and B lymphocytes. Similarly, F-actin polymerization in response to stimulation (fMLF) was reduced.

Major neutrophil dysfunction:

Migration: greatly reduced chemotactic response

ROS production and oxidative burst: The production of ROS (reactive oxygen species), whether intracellular or extracellular, and the production of H₂O₂ (assessed by DHR) were reduced in response to stimulation. This contrasts with previous reports that did not note any defects in ROS production.

NETs (Neutrophil Extracellular Traps): The formation of NETs, a crucial immune defense mechanism requiring intact actin cytoskeleton rearrangement, was impaired.

Transcriptomic analysis of neutrophils provided support for the clinical inflammatory observations, revealing downregulation of cytoskeletal genes but, concomitantly, upregulation of inflammatory pathways, including the NFkB pathway, TNFα, and a signature typical of inflammatory bowel disease (IBD). These results may partly explain the inflammatory manifestations observed in the patient.

In conclusion, the authors report here the first case of MKL1 deficiency associated with composite heterozygous variants, significantly broadening the known phenotypic spectrum. The association of a marked autoinflammatory phenotype with a less severe immune deficiency highlights the diversity and complexity of actinopathies. As illustrated here, the full phenotype of these diseases probably remains to be discovered, justifying further clinical and functional investigations.

Pediatric Allergy Immunology - 2025 - Li - Novel compound heterozygous MRTFA gene variants.

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