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