Human Molecular Genetics Advance Access published online on June 15, 2004
Human Molecular Genetics, doi:10.1093/hmg/ddh185
© 2004 by Oxford University Press
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1 The Institute for Neuromuscular Research, The Children's Hospital at Westmead, Australia; Discipline of Paediatrics and Child Health, Faculty of Medicine, University of Sydney, Australia
* To whom correspondence should be addressed. E-mail: sandrac3{at}chw.edu.au.
We have studied a cohort of nemaline myopathy (NM) patients with mutations in the muscle Transfection of C2C12 myoblasts with mutant actinEGFP constructs resulted in abnormal cytoplasmic and intranuclear actin aggregates. Intranuclear aggregates were observed with V163L-, V163M- and R183G-actinEGFP constructs, and modelling shows these residues to be adjacent to the nuclear export signal of actin. V163L and V163M actin mutants are known to cause intranuclear rod myopathy, however intranuclear bodies were not reported in Patient R183G. Transfection studies in C2C12 myoblasts showed significant alterations in the ability of V136L and R183G actin mutants to polymerize and contribute to insoluble actin filaments. Thus, we provide direct evidence for a dominant-negative effect of mutant actin in NM. In vitro studies suggest that abnormal folding, altered polymerization, and aggregation of mutant actin isoforms are common properties of NM ACTA1 mutants. Some of these effects are mutation-specific, and likely result in variations in the severity of muscle weakness seen in individual patients. A combination of these effects contributes to the common pathological hallmarks of NM, namely intranuclear and cytoplasmic rod formation, accumulation of thin filaments and myofibrillar disorganization.
Article
Evidence for a dominant-negative effect in ACTA1 nemaline myopathy caused by abnormal folding, aggregation and altered polymerization of mutant actin isoforms
2 Centre for Neuromuscular and Neurological Disorders, University of Western Australia, Australian Neuromuscular Research Institute, Queen Elizabeth II Medical Centre, Nedlands, Western Australia; MRC Functional Genetics Unit, Department of Human Anatomy and Genetics, University of Oxford, UK
3 The Institute for Neuromuscular Research, The Children's Hospital at Westmead, Australia
4 Department of Pathology, University of Geneva, Geneva, Switzerland
5 MRC Functional Genetics Unit, Department of Human Anatomy and Genetics, University of Oxford, UK
6 Centre for Neuromuscular and Neurological Disorders, University of Western Australia, Australian Neuromuscular Research Institute, Queen Elizabeth II Medical Centre, Nedlands, Western Australia
7 The Institute for Neuromuscular Research, The Children's Hospital at Westmead, Locked Bag 4001, Westmead, NSW 2145, Australia
Abstract 
-skeletal actin gene (ACTA1). Immunoblot analysis of patient muscle demonstrates increased 
-filamin, myotilin, desmin and -actinin in many NM patients, consistent with accumulation of Z line-derived nemaline bodies. We demonstrate that nebulin can appear abnormal secondary to a primary defect in actin, and show by isoelectric focusing that mutant actin isoforms are present within insoluble actin filaments isolated from muscle from two ACTA1 NM patients.
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