Dysimmune Actinopathies: Better Understanding These Rare Diseases in the Middle East and North Africa

Article title: Clinical and molecular findings in actin-related inborn errors of immunity: the middle East and North Africa registry

First author: Zahra Chavoshzadeh

Journal: Front Genet.

Link to the article: https://pubmed.ncbi.nlm.nih.gov/40860338/

Author of the abstract: Philippe Mertz

Actinopathies are an emerging group of primary immunodeficiencies linked to abnormalities in the genes that regulate the actin cytoskeleton. These proteins control essential immune functions such as cell migration, tissue infiltration, and immunological synapse formation. Clinically, they are associated with severe and recurrent infections, allergic manifestations, cytopenias (particularly thrombocytopenia and/or abnormal mean platelet volume), autoimmunity, and sometimes malignancies.

The MENA (Middle East and North Africa) region has a high prevalence of these diseases, due in particular to a high frequency of consanguineous marriages. The aim of this retrospective multicenter study was to describe the clinical, immunological, and genetic characteristics and therapeutic approaches used in patients with actinopathy.

The authors proposed a classification of actinopathies into three main groups, according to the mechanisms affected (see Figure 1A extracted from the article). For the record, actin polymerization is essential for the formation of cell protrusions and depends mainly on two pathways associated with the RHO GTPases RAC2 and CDC42:

The group of RAC2 pathway regulators (in blue), which activates the ARP2/3 complex and induces lamellipodia formation;

The group of CDC42 pathway regulators (in red), which activates the WAVE complex and generates filopodia;

A third group mainly includes abnormalities in actin transcription factors or their regulators (in green), such as CEBPE, WDR1, or MKL1.

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A total of 503 patients from 17 countries were included. The median age at symptom onset was 4 months, and the median time to diagnosis was 19 months. Overall mortality was 23%, mainly due to infectious complications and cancers.

The most common initial presentations were allergic manifestations (33.7%), infections (32%), and hemorrhages (16.8%). Throughout life, infections predominated (90%), especially respiratory (72%) and skin (48%) infections. Eczema was the most common allergic manifestation (67.9%). Cytopenias (42.7%), lymphoproliferative disorders (19.1%), and lymphomas (5.9%) completed the spectrum.

Among the 391 patients who received a genetic diagnosis, the genes most commonly involved were DOCK8 (53.8%), WAS (n=24.6%), and CARMIL2 (4.3%). It should be noted that no patients with CDC42 mutations were included in the CDC42 pathway regulator group.

Hematopoietic stem cell transplantation (HSCT) was performed in 24% of patients, significantly improving survival in WAS, DOCK8, and DOCK2 deficiencies. Immunoglobulin replacement (89.4%) and antibiotic prophylaxis (93%) were almost systematic.

The authors then looked at the differences in presentation between the different groups. The main differences are shown in the figure opposite.

VPM : volume plaquettaire moyen

Key messages

1. Actinopathies are most often revealed in early childhood through severe infections (respiratory +++) and allergies (eczema, atopic dermatitis), with an overall mortality rate of around 25%. Platelet counts may be normal in the vast majority of patients (48–94% depending on the group).

   
   

2. Variants affecting the CDC42 pathway are associated with earlier onset, a more severe phenotype, and higher mortality than those affecting the RAC2 pathway, which have a later onset, often marked by lymphoproliferation.

   
   

3. Hematopoietic stem cell transplantation (HSCT) is a key therapeutic option, particularly beneficial for DOCK8, WAS, and DOCK2 deficiencies, highlighting the importance of early diagnosis and rapid referral to a center of expertise.

Clinical and molecular findings in actin-related inborn errors of immunity: the middle Eas.

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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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Discovery of a new actinopathy linked to the CCDC88A gene, associated with neurological and immune disorders

Article title: Genome sequencing reveals CCDC88A variants in malformations of cortical development and immune dysfunction

First author:Johanna Lehtonen

Journal: Human Molecular Genetics

Link to the article: https://pubmed.ncbi.nlm.nih.gov/40401444/

Author of the abstract: Philippe Mertz

Three key points to remember:

1. Two new variants of CCDC88A have been identified in two full-term children born to unrelated parents of Finnish origin, who suffer from cortical malformations, microcephaly, and epilepsy. This gene encodes the protein girdin, which can bind to actin and acts as a regulator of the actin cytoskeleton.

2. Their fibroblasts show qualitative and functional abnormalities of the actin cytoskeleton.

3. This actinopathy is associated with immune disorders, including an associated immune deficiency, and probably also with inflammatory disorders (inflammatory colitis in one of the two patients).

Actinopathies are a group of rare genetic diseases in which abnormalities in the dynamics of the actin cytoskeleton disrupt various cellular functions, particularly in the immune and nervous systems. They are associated with complex clinical phenotypes, which may include manifestations such as malformations and dysmorphic syndrome, neurodevelopmental delay, manifestations such as primary immunodeficiency, or autoimmune and autoinflammatory manifestations.

The CCDC88A gene encodes the protein girdin, a protein capable of binding directly to actin and participating in the regulation of its functions. It acts as a multifunctional adapter essential for the organization of the actin cytoskeleton, PI3K-AKT signaling, cell migration, and the regulation of the balance between proliferation and migration. Girdin also interacts with many proteins, including EGFR, and is involved in the formation of the immunological synapse, autophagy, and vesicular trafficking.

In this study, the authors report on two patients, a brother and sister, born to two unrelated parents of Finnish origin, who suffered from cortical developmental malformations, postnatal microcephaly, severe epilepsy, profound intellectual disability, and increased susceptibility to infections. Whole genome sequencing revealed composite heterozygous variants of CCDC88A in both children, including a missense mutation (p.Asp310Ala) and an intragenic deletion of three exons (p.E508*), which had not been reported previously. Simple heterozygous carriage of these variants was detected in asymptomatic individuals in the family.

Functional analysis of patients' fibroblasts has enabled the cellular consequences of girdin deficiency to be characterized for the first time. The mutated cells show increased proliferation, decreased migration, reduced cell size, disorganization of the actin cytoskeleton (elongated, aggregated, and poorly reticulated bundles), decreased focal adhesions, and perinuclear accumulation of endolysosomal organelles. These phenotypes were reproduced in fibroblast lines knocked out for CCDC88A by CRISPR-Cas9, confirming that this is an actinopathy associated with loss of girdin function.

Immunologically, girdin is mainly expressed by monocytes, macrophages, and dendritic cells, and less so by T lymphocytes. Patients showed marked susceptibility to respiratory infections, defective vaccine response, moderate B lymphopenia, reduced numbers of monocyte-like and plasmacytoid dendritic cells, and decreased regulatory T cells. One patient also had chronic inflammatory bowel disease diagnosed on the basis of compatible abdominal symptoms and elevated fecal calprotectin. Interestingly, girdin deficiency leads to a hyperreactive immune response by macrophages in the mouse model of dextran sodium sulfate-induced colitis (a model that also presents with a shortened colon and significant weight loss). These data support the existence of a combined immune deficiency affecting innate and adaptive immunity, and associated inflammatory manifestations.

CCDC88A had already been implicated in neurodevelopmental encephalopathies caused by homozygous truncating variants, but this is the first time that an immune dysfunction phenotype has been authenticated in patients carrying mutations in this gene. It is also the first study to demonstrate, through functional approaches on primary cells and CRISPR models, that CCDC88A variants induce true immunoactinopathy.

Genome sequencing reveals CCDC88A variants.pdf

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