Variants in exons 5 and 6 of ACTB cause syndromic thrombocytopenia

Area of Science:

• Genetics
• Cell Biology
• Developmental Biology

Background:

• Germline mutations in ACTB, encoding β-cytoplasmic actin (CYA), are typically linked to Baraitser-Winter Cerebrofrontofacial syndrome (BWCFF).
• The 3'-coding region of ACTB has not been extensively studied for pathogenic variants.

Purpose of the Study:

• To identify and characterize novel ACTB variants and their associated clinical phenotypes.
• To elucidate the molecular mechanisms underlying the observed clinical features, particularly thrombocytopenia.

Main Methods:

• Genetic sequencing to identify ACTB variants in affected patients.
• Analysis of patient-derived fibroblasts to assess β-CYA filament populations and actin binding protein (ABP) recruitment.
• In silico modeling to predict protein interactions.
• Examination of megakaryocytes and thrombocytes to evaluate cytoskeleton organization.

Main Results:

• Six patients presented with previously undescribed heterozygous ACTB variants in the 3'-coding region.
• Clinical features included mild developmental disability, microcephaly, and thrombocytopenia with platelet anisotropy.
• Patient cells showed altered β-CYA filament dynamics and increased recruitment of thrombocytopenia-associated ABPs.
• ACTB mutations impaired microtubule organization, inhibiting platelet maturation.

Conclusions:

• A novel ACTB-associated clinical syndrome distinct from BWCFF is defined.
• Genotype-phenotype correlations for these ACTB variants are established.
• Molecular mechanisms involving actin and microtubule cytoskeleton disruption in thrombocytopenia are delineated.