Nowak KJ, Ravenscroft G, Laing NG. Skeletal muscle α-actin
diseases (actinopathies): pathology and mechanisms. Acta Neuropathol. 2013 Jan;125(1):19-32.
Abstract
Mutations in the skeletal muscle α-actin gene (ACTA1) cause
a range of congenital myopathies characterised by muscle weakness and specific
skeletal muscle structural lesions. Actin accumulations, nemaline and
intranuclear bodies, fibre-type disproportion, cores, caps, dystrophic features
and zebra bodies have all been seen in biopsies from patients with ACTA1
disease, with patients frequently presenting with multiple pathologies.
Therefore increasingly it is considered that these entities may represent a
continuum of structural abnormalities arising due to ACTA1 mutations. Recently
an ACTA1 mutation has also been associated with a hypertonic clinical
presentation with nemaline bodies. Whilst multiple genes are known to cause
many of the pathologies associated with ACTA1 mutations, to date actin
aggregates, intranuclear rods and zebra bodies have solely been attributed to
ACTA1 mutations. Approximately 200 different ACTA1 mutations have been
identified, with 90 % resulting in dominant disease and 10 % resulting in
recessive disease. Despite extensive research into normal actin function and
the functional consequences of ACTA1 mutations in cell culture, animal models
and patient tissue, the mechanisms underlying muscle weakness and the formation
of structural lesions remains largely unknown. Whilst precise mechanisms are
being grappled with, headway is being made in terms of developing therapeutics
for ACTA1 disease, with gene therapy (specifically reducing the proportion of
mutant skeletal muscle α-actin protein) and pharmacological agents showing
promising results in animal models and patient muscle. The use of small
molecules to sensitise the contractile apparatus to Ca(2+) is a promising
therapeutic for patients with various neuromuscular disorders, including ACTA1
disease.
Goebel HH, Laing NG. Actinopathies and myosinopathies. Brain
Pathol. 2009
Jul;19(3):516-22.
Abstract
The currently recognized two forms of "anabolic"
protein aggregate myopathies, that is, defects in development, maturation and
final formation of respective actin and myosin filaments encompass
actinopathies and myosinopathies. The former are marked by mutations in the
ACTA1 gene, largely of the de novo type. Aggregates of actin filaments are
deposited within muscle fibers. Early clinical onset is often congenital; most
patients run a rapidly progressive course and die during their first 2 years of
life. Myosinopathies or myosin storage myopathies also commence in childhood,
but show a much more protracted course owing to mutations in the myosin heavy
chain gene MYH7. Protein aggregation consists of granular material in muscle
fibers and few, if any, filaments.
Feng JJ, Marston S. Genotype-phenotype correlations in ACTA1
mutations that cause congenital myopathies. Neuromuscul Disord. 2009
Jan;19(1):6-16.
Abstract
Mutations in the skeletal muscle actin gene, ACTA1 are
responsible for up to 20% of congenital myopathies with a variety of
pathologies that includes nemaline myopathy, intranuclear rod myopathy, actin
myopathy and congenital fibre type disproportion. In their review of 2003,
Sparrow et al. considered how these actin mutations might affect muscle
function at the molecular level and thus cause the disease. Since then several
laboratories have taken up the challenge of investigating genotype-phenotype
relationships experimentally. The objective of this review is to assess the
current state of our understanding of the molecular mechanisms of skeletal
myopathies and the prospects for future therapies based on this knowledge.
Thirty congenital myopathy-causing ACTA1 mutations have been studied using a
range of biochemical and in vitro approaches. They showed diverse molecular
defects, and there is no obvious pattern seen in mutations resulting in the
same histopathology.
Inspired by a patient.
Inspired by a patient.
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