ACTB Loss-of-Function Mutations Result in a Pleiotropic Developmental Disorder

Area of Science:

• Genetics
• Developmental Biology
• Human Disease

Background:

• ACTB encodes β-actin, a crucial cytoskeletal protein.
• Gain-of-function mutations in ACTB are linked to Baraitser-Winter syndrome (BRWS).
• The effects of ACTB loss-of-function mutations remained unclear.

Purpose of the Study:

• To investigate the consequences of heterozygous ACTB loss-of-function mutations.
• To describe a novel malformation syndrome associated with ACTB mutations.
• To elucidate the biological mechanisms underlying ACTB haploinsufficiency.

Main Methods:

• Clinical evaluation of 33 individuals with ACTB deletions or nonsense/frameshift mutations.
• Analysis of ACTB mRNA levels in patient-derived cells.
• In vitro studies using patient fibroblasts and siRNA knockdown in wild-type cells.

Main Results:

• Identified a distinct syndrome in 33 individuals with developmental delay, intellectual disability, organ malformations, and specific facial features.
• Observed decreased ACTB mRNA levels and altered cellular functions (shape, migration, proliferation) in affected individuals.
• Demonstrated reduced nuclear β-actin and altered cell-cycle gene expression.

Conclusions:

• Heterozygous loss-of-function ACTB mutations cause a distinct pleiotropic malformation syndrome.
• Reduced β-actin levels impair cell shape, migration, proliferation, and gene expression.
• This impacts critical organ development, including the brain, heart, and kidneys.