Genome sequencing reveals CCDC88A variants in malformations of cortical development and immune dysfunction
Johanna Lehtonen1,2,3,4, Anna H Hakonen5, Antti Hassinen2
1Centre for Molecular Medicine Norway (NCMM), University of Oslo, Oslo Science Park, Gaustadalléen 2, Oslo 0349, Norway.
Human Molecular Genetics
|May 22, 2025
Summary
Genetic variants in CCDC88A cause malformations of cortical development (MCD), microcephaly, and epilepsy. This study identifies compound heterozygous variants in siblings, revealing cellular and immune defects linked to girdin deficiency.
Area of Science:
- Genetics and Molecular Biology
- Developmental Neuroscience
- Immunology
Background:
- Malformations of cortical development (MCDs) are a heterogeneous group of genetic disorders affecting brain formation.
- CCDC88A, encoding the protein girdin, plays a crucial role in cellular functions including actin remodeling and proliferation.
- Previous research linked homozygous truncating CCDC88A variants to severe neurodevelopmental disorders.
Purpose of the Study:
- To determine the genetic cause of MCD, microcephaly, epilepsy, intellectual disability, and immune susceptibility in two siblings.
- To investigate the cellular and immunological consequences of identified CCDC88A variants.
- To validate the pathogenic mechanisms through cellular models.
Main Methods:
- Whole genome sequencing to identify genetic variants in affected siblings.
- Western blot analysis to assess protein expression of girdin variants.
- Cellular assays including proliferation, wound healing, and high-content imaging.
- CRISPR-Cas9 gene editing to create fibroblast knockout models.
- Flow cytometry to analyze immune cell populations.
Main Results:
- Compound heterozygous variants (a missense variant and an intragenic deletion) in CCDC88A were identified in the siblings.
- Girdin-deficient fibroblasts exhibited altered morphology, disrupted actin remodeling, and perinuclear organelle accumulation.
- Girdin deficiency led to increased fibroblast proliferation but decreased migration.
- Siblings showed reduced monocytoid and plasmacytoid dendritic cells, indicating compromised immunity.
- CRISPR-Cas9 generated knockout cells replicated the observed cellular phenotypes.
Conclusions:
- This study reports the first association of CCDC88A missense and deletion variants with MCD.
- Girdin deficiency underlies significant cellular alterations, including changes in cell morphology and proliferation-migration dynamics.
- Compromised immune cell function is a notable consequence of girdin deficiency.
- The findings reinforce the pathogenic role of CCDC88A variants in neurodevelopmental and immune disorders.
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