Beta-actin (ACTB), one of the actin isoforms, is an important cytoskeletal protein. Mutations in the ACTB gene were found in Baraitser-Winter cerebrofrontofacial syndrome. In one patient, immunodeficiency of neutrophils was identified.
Actins are a family of highly conserved cytoskeletal proteins that play fundamental roles in nearly all aspects of eukaryotic cell biology. The ability of a cell to divide, move, endocytose, generate contractile force, and maintain shape is reliant upon functional actin-based structures. The importance of the cytoskeleton in mounting a successful immune response is evident from the wide range of defects that occur in actin-related primary immunodeficiencies (PIDs). Actin isoforms are grouped according to expression patterns: muscle actins predominate in striated and smooth muscle (ACTA1 and ACTA2, respectively), whereas the two cytoplasmic non-muscle actins, gamma-actin (ACTG1) and beta-actin (ACTB), are found in all cells and differ by only four amino acids at their conserved N-terminal ends. Beta-actin protein is encoded by ACTB located at 7p22.1 and has five known splice variants (Moulding et al. 2013).
Compared with myopathy and angiopathy-associated defects of muscle isoactins, mutations of beta-actin and gamma-actin isoforms lead to a wider spectrum of diseases that include deafness, cancer, and skeletal and developmental disorders.
Several different nonlethal mutations of ACTB were identified in Baraitser-Winter cerebrofrontofacial syndrome (Verloes et al. 2015). This is an autosomal dominant trait with craniofacial, visceral, and muscular involvement due to gain-of-function mutations in ACTB or ACTG1. Major features include hypertelorism, bilateral ptosis, ocular colobomata, metopic ridging, and trigonocephaly. The nose is wide, short, and upturned. Skeletal defects comprise short stature, dorsal kyphosis, anteverted shoulders, and limited joint movements with slightly flexed elbows and knees. Neurological anomalies occur in the form of motor delay, intellectual deficiency, and agyria or pachygyria. Other ACTB mutations were found to be associated with juvenile-onset dystonia (Procaccio et al. 2006), which is a severe autosomal dominant disorder of movement with involuntary muscle contractions, associated with neurosensory hearing loss, pronounced facial defects with bilateral ptosis and hypertelorism, intellectual deficiency, and structural brain defects. Perhaps, however, juvenile-onset dystonia should merely be taken as a variant within the spectrum of Baraitser-Winter cerebrofrontofacial syndrome (Rivière et al. 2012).
To date there has been only one case report of immunodeficiency secondary to ACTB mutation (Nunoi et al. 1999). A 12-year-old female patient presented with recurrent infections, photosensitivity, and mental retardation. She also had abnormalities in neutrophil chemotaxis, superoxide production, and membrane potential response. Laboratory investigation of peripheral blood cells identified an abnormal actin protein. Sequencing of the actin gene revealed a heterozygous G-1174 to A substitution, predicting a glutamic acid 364 to lysine substitution in beta-actin. Though no defect in cell-free polymerization of actin was detected, this defect lies in a domain important for binding to profilin and other actin-regulatory molecules, and the mutant actin bound to profilin less efficiently than normal actin did. By 15 years of age, she had developed cardiomegaly, hepatomegaly, and hypothyroidism. At that time, she presented with persistent fevers, and, despite intensive therapy, she died from septicemia (Hundt et al. 2014).
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