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
Center for Molecular and Mitochondrial Medicine and Genetics, University of California, Irvine, CA 92697, USA.
Am J Hum Genet. 2006 Jun;78(6):947-60. doi: 10.1086/504271. Epub 2006 Apr 21.
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.
肌动蛋白是主要的丝状细胞骨架分子之一，参与多种细胞功能。虽然肌肉肌动蛋白突变与骨骼肌和心肌病之间的关联已有充分记录，但关于非肌肉肌动蛋白基因突变导致人类疾病的报道却很少。我们在编码β-肌动蛋白的基因中发现了一个错义点突变，该突变导致第183位的精氨酸被色氨酸取代。疾病表型包括发育性中线畸形、感音神经性听力损失以及单卵双胞胎中迟发性全身性肌张力障碍综合征。对从一名受影响患者获得的淋巴母细胞系进行的细胞研究表明，肌动蛋白细胞骨架存在形态异常，并且在肌动蛋白单体螯合剂拉春库林A的作用下，肌动蛋白解聚动力学发生改变。在表达突变型肌动蛋白的NIH 3T3细胞中也观察到对拉春库林A的抗性。这些发现表明，非肌肉肌动蛋白的突变可能与广泛的发育畸形和/或神经异常如肌张力障碍有关。
