A Mutation of β-Actin That Alters Depolymerization Dynamics Is Associated with Autosomal Dominant Developmental Malformations, Deafness, and Dystonia

Abstract

Actin, one of the major filamentous cytoskeletal molecules, is involved in a variety of cellular functions. Whereas an association between muscle actin mutations and skeletal and cardiac myopathies has been well documented, reports of human disease arising from mutations of nonmuscle actin genes have been rare. We have identified a missense point mutation in the gene coding for beta -actin that results in an arginine-to-tryptophan substitution at position 183. The disease phenotype includes developmental midline malformations, sensory hearing loss, and a delayed-onset generalized dystonia syndrome in monozygotic twins. Cellular studies of a lymphoblastoid cell line obtained from an affected patient demonstrated morphological abnormalities of the actin cytoskeleton and altered actin depolymerization dynamics in response to latrunculin A, an actin monomer-sequestering drug. Resistance to latrunculin A was also observed in NIH 3T3 cells expressing the mutant actin. These findings suggest that mutations in nonmuscle actins may be associated with a broad spectrum of developmental malformations and/or neurological abnormalities such as dystonia.

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

“…Moreover, because the human cytoplasmic actins are functional in Arabidopsis, missense mutations in these human actins that are associated with a large number of diseases, including blindness, deafness, myopathies, immune deficiency, and aberrant kidney function, could be easily tested in this plant model. For example, the influence of dominant missense mutations in b-actin on the structure of lamellapodia in lymphoblasts (Procaccio et al, 2006) and in g-actin on the maintenance of stereocilia in the ear (Morín et al, 2009) might be studied in Arabidopsis root hairs. By contrast, examining actin functions using transgenic mouse models would be orders of magnitude more expensive and time consuming.…”

“…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).…”

Baraitser–Winter cerebrofrontofacial syndrome: delineation of the spectrum in 42 cases

“…Mutation analysis was performed using Sanger sequencing in four laboratories (initial research in Seattle and Nijmegen, routine in Paris and Dresden). We gathered 42 patients, including the 16 patients briefly reported in our first paper, 7 four newly published patients with mutations 6,8,9 and twins with an ACTB mutation, who developed dystonia in late childhood and died in their early twenties, 10,11 as, retrospectively, the diagnosis in these patients was compatible with BWCFF (B26 and B27).…”

Severe forms of Baraitser–Winter syndrome are caused by ACTB mutations rather than ACTG1 mutations

“…Although not a typical feature of BRWS, cleft lip/palate has already been reported in connection with ACTB point mutations 10 and deletions of the whole gene. 1 Cleft lip/palate was also seen in a BRWS patient carrying an ACTG1 mutation (58431 in Rivière et al, 1 ) and thus should be included in the clinical presentation of BRWS spectrum.…”