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

• Published in: American journal of human genetics 2006-06, Vol.78 (6), p.947-960
• Main Authors: Procaccio, Vincent, Salazar, Gloria, Ono, Shoichiro, Styers, Melanie L., Gearing, Marla, Davila, Antonio, Jimenez, Richard, Juncos, Jorge, Gutekunst, Claire-Anne, Meroni, Germana, Fontanella, Bianca, Sontag, Estelle, Sontag, Jean Marie, Faundez, Victor, Wainer, Bruce H.
• Format: Article
• Language: English
• Subjects: Actins - analysis; Actins - drug effects; Actins - genetics; Amino Acid Sequence; Amino Acid Substitution; Animals; Biological and medical sciences; Bridged Bicyclo Compounds, Heterocyclic - pharmacology; Deafness - genetics; Drug Resistance; Dystonia - genetics; Ear, auditive nerve, cochleovestibular tract, facial nerve: diseases, semeiology; General aspects. Genetic counseling; Hearing Loss, Sensorineural - genetics; Humans; Male; Medical genetics; Medical sciences; Mice; Microsatellite Repeats - genetics; Molecular Sequence Data; Mutation, Missense; Nervous system (semeiology, syndromes); Nervous system as a whole; Nervous System Malformations - genetics; Neurology; NIH 3T3 Cells; Non tumoral diseases; Otorhinolaryngology. Stomatology; Phalloidine - metabolism; Stress Fibers - ultrastructure; Syndrome; Thiazoles - pharmacology; Thiazolidines; Transfection; Twins, Monozygotic
• ISSN: 0002-9297; 1537-6605
• DOI: 10.1086/504271

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 β-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.