A heterozygous mutation of β-actin associated with neutrophil dysfunction and recurrent infection

Abstract

A human disorder caused by mutation in nonmuscle actin has not been reported. We report here a variant of nonmuscle actin in a female patient with recurrent infections, photosensitivity, and mental retardation. She also had abnormalities in neutrophil chemotaxis, superoxide production, and membrane potential response. Two-dimensional PAGE analysis of proteins from neutrophils and other cell types from this patient demonstrated a unique protein spot migrating at 42 kDa with pI shifted slightly to neutral relative to normal ␤-and ␥-actin. Digestion peptide mapping and Western blotting showed this spot to be an abnormal actin. A full-length cDNA library was constructed by using mRNA from patient's cells and cDNA encoding the mutant ␤-actin molecule was identified by an in vitro translation method. Sequencing of the clones demonstrated a G-1174 to A substitution, predicting a glutamic acid-364 to lysine substitution in ␤-actin and eliminating a HinfI DNase restriction site found in normal ␤-actin sequence. By HinfI digestion and by sequencing, the mutation in one allele of patient's genomic DNA was confirmed. 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. In fact, the mutant actin bound to profilin less efficiently than normal actin did. Heterozygous expression of mutant ␤-actin in neutrophils and other cells of this patient may act in a dominant-negative fashion to adversely affect cellular activities dependent on the function of nonmuscle actin.

The S100A8/A9 protein as a partner for the cytosolic factors of NADPH oxidase activation in neutrophils

“…Most significantly, abnormalities in O 2 -production have been found in neutrophils of a patient carrying a mutation in nonmuscle actin [29]. These data and ours on S100A8/A9 strongly suggest that there exists a complex array of interactions between the classical phox components of the oxidase complex and other molecular protein species in phagocytic cells.…”

Quadriceps myopathy caused by skeletal muscle-specific ablation of βcyto-actin

“…However, a QM would probably only be one of many symptoms associated with expression of a mutant  cyto -actin due to its ubiquitous expression. In fact, two mutations in the ACTB gene were associated with numerous physiological deficits ranging from immunodeficiency (Nunoi et al, 1999) to dystonia and hearing loss (Procaccio et al, 2006). Both the complexity of symptoms as well as premature death might have precluded detection of a QM in these patients.…”

Plant Vegetative and Animal Cytoplasmic Actins Share Functional Competence for Spatial Development with Protists

“…In Arabidopsis, deficiency in one of the three constitutively expressed actins, ACT7, severely impairs root organ development and results in minor shoot defects, whereas lack of the other two constitutive actins, ACT2 and ACT8, affects root hair cell tip growth (Kandasamy et al, 2009). Missense mutations in human actins are also associated with a variety of gene-specific developmental pathologies, including skeletal and smooth muscle myopathies (Sparrow et al, 2003;Donnell et al, 2008), midline malformations (Procaccio et al, 2006), neutrophil dysfunction (Nunoi et al, 1999), and deafness (Zhu et al, 2003;Bryan et al, 2006).…”