Download More surprises in sarcomeric protein diseases

doi:10.1093/brain/awm073
Brain (2007), 130, 1453^1455
SCIENTIF IC COMMENTARY
More surprises in sarcomeric protein diseases
In this issue of Brain, three papers (Wallgren-Pettersson
et al., Griggs et al. and Walter et al.) expand the horizons of
skeletal muscle diseases caused by mutations in sarcomeric
proteins.
Two of the papers (Wallgren-Pettersson et al., and Griggs
et al.) deal solely with distal myopathies. One of the most
unexpected discoveries in the sarcomeric protein disease
field has been that mutations in sarcomeric proteins can
cause distal myopathies. Each distal myopathy preferentially
affects what can be a bizarre collection of specific, restricted
muscles. In the early-onset distal myopathy, MPD1, this
starts with the tibialis anterior and later extends to the
flexor hallucis longus, long finger extensors, sternocleidomastoids and the medial head of the gastrocnemius
(Lamont et al., 2006). What sort of gene can do that to a
patient? One might think of genes involved in positional
information. However, we now know that specific mutations in the rod-domain of the slow myosin heavy chain,
the myosin expressed in every slow skeletal muscle fibre and
in the heart, cause this disease (Meredith et al., 2004).
The pathophysiological cascade from myosin mutation to
disease phenotype remains a mystery. Equally, mutations in
titin, expressed in every muscle fibre in the body, cause
tibial muscular dystrophy—a late onset distal myopathy
affecting another restricted group of muscles, including
some of the same muscles as MPD1 (Hackman et al., 2002).
In the first paper, Wallgren-Pettersson et al. (page 1465)
report that homozygosity for missense mutations in nebulin
causes an early onset mild distal myopathy. WallgrenPettersson and her colleagues had previously shown that
mutations in nebulin are the commonest cause of recessive
nemaline myopathy (Pelin et al., 1999). Nebulin nemaline
myopathy, like other congenital myopathies, affects proximal muscles more than distal muscles (Wallgren-Pettersson
et al., 2004). The nebulin mutations that cause nemaline
myopathy are most often nonsense, frameshift or splice site
mutations, mutations that should considerably disrupt the
nebulin protein (Pelin et al., 2002; Lehtokari et al., 2006).
However, in some nemaline myopathy patients, one of
these disruptive mutations was found to cause disease in
association with a missense mutation (generally less
disruptive to protein function) on the other nebulin allele
(Pelin et al., 2002; Lehtokari et al., 2006). WallgrenPettersson et al. now show that homozygosity for these very
same missense mutations causes an early-onset distal
myopathy, phenotypically similar to MPD1. This research
could only have been accomplished in Finland, where the
populations of distal myopathy and nemaline myopathy
patients are so well characterized and where the genetic
isolate that is the Finnish population, lends itself to such
discoveries. Again we do not know how homozygous
nebulin missense mutations cause a restricted distal
myopathy, while the same missense mutations in conjunction with more deleterious nonsense, frameshift or splicesite mutations cause nemaline myopathy, preferentially
affecting more proximal muscles.
The second paper by Griggs et al. (page 1477), which also
at least in part comes from Finland through the contribution
of Bjarne Udd’s laboratory, demonstrates that the seminal
Markesbery–Griggs distal myopathy family, first described in
1974 (Markesbery et al., 1974) has the A165V ZASP
mutation previously described in myofibrillar myopathy
patients (Selcen and Engel, 2005). This result is something of
a surprise, since for some time now it has been suggested
that the disease in the Markesbery-Griggs family was allelic
to tibial muscular dystrophy (Hackman et al., 2002) at the
titin locus on chromosome 2. Griggs et al. explain that
the linkage to the titin locus proved incorrect and that the
identification of a ZASP mutation in this family highlights
the difficulties of linkage analysis in late-onset diseases. As
Griggs et al. indicate, ‘Relying on linkage results is usually,
but not always, good enough.’ Griggs et al. conclude that the
muscle pathology findings in the Markesbery–Griggs family
were the clue to correcting the molecular genetic approach.
Griggs et al. moved to a candidate gene approach instead of
further pursuing a borderline linkage result that had caused
a fruitless search for a disease-causing mutation in the giant
titin gene. Mutations in a number of proteins: ZASP,
desmin, myotilin and a-B crystallin are all known to cause
myofibrillar myopathy, which may display a distal phenotype (Selcen and Engel, 2005). Sequencing of the ZASP gene
in the Markesbery–Griggs patients identified the A165V
mutation. Griggs et al. also found the same ZASP A165V
mutation in two isolated distal myopathy patients, one from
France and one from the UK, that had both been referred for
investigation as possible titinopathy patients. Analysis of
these patients, one patient from the Markesbery-Griggs
family and three patients with the same A165V mutation
described by Selcen and Engel (2005), demonstrated a
conserved small, 34 kb, haplotype around the ZASP A165V
mutation, indicating a founder mutation.
The third of these papers, by Walter et al. (page 1485), is
only partly concerned with distal myopathy but echoes the
results of Griggs et al. Walter et al. demonstrate that the
scapuloperoneal syndrome in the German family originally
described by Kaeser in 1965 (Kaeser, 1965) is caused by the
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Brain (2007), 130, 1453^1455
same R350P mutation in desmin that they had previously
identified in a German family with distal myopathy. They
found the R350P mutation in three further families all of
German descent, making five families in total, and showed
a common conserved haplotype around the desmin gene in
all five families, again suggesting a founder mutation.
In total they examined 15 affected individuals in the five
families and found highly variable clinical phenotypes:
mostly a limb girdle muscular dystrophy phenotype, or a
distal myopathy phenotype in addition to the scapuloperoneal syndrome. Close to 50% of the patients had
cardiomyopathy, and three male patients had gynecomastia.
The histopathology was also highly variable in different
patients. Walter et al. conclude that the clinical and
histopathological phenotypes cannot be due to the desmin
R350P mutation alone but must be influenced by other
genetic and epigenetic factors including gender. Desmin is
the predominant intermediate filament protein of skeletal
and heart muscle. It binds to Z-discs and aligns the Z-discs
in neighbouring myofibrils. Presumably variations in this
environment determine the precise phenotype in each
patient.
I think the fact that distal myopathies can be caused by
mutations in sarcomeric proteins and sarcomere-associated
proteins like desmin is telling us that there are layers of
complexity to muscle biology that we know little about. All
skeletal muscles are not created equal. Individual skeletal
muscles exist in different locations, may contain different
proteins (von der Hagen et al., 2005) and are subjected to
different environments. The key to understanding the
pathophysiology of the distal myopathies must lie in these
differences.
There are currently no treatments for the distal
myopathies. However, supportive measures including physiotherapy and orthotic appliances can be extremely
beneficial. Developing treatments for the distal myopathies
originating in the sarcomere, the fundamental unit of
muscle contraction, presents a daunting challenge. Take
titin as a paradigm for sarcomeric protein diseases. Titin is
the giant protein ruler stretching across the entire half
sarcomere from Z-line to M-line. There are multiple splice
isoforms, each with a coding region greater than 100 kb
(10 times the size of dystrophin) and different diseases are
caused by different mutations in different parts of titin
(Hackman et al., 2003). The other sarcomeric proteins
associated with muscle diseases also tend to be large and
have different diseases associated with them. Perhaps the
best way to overcome the sarcomeric protein diseases may
be by muscle transplantation in the form of myoblast or
stem cell therapy since these approaches, if successful, could
be used to treat multiple mutations in multiple genes
(Kunkel et al., 2006). Alternatively, if each step in the
pathophysiological cascade from the mutated protein to the
disease could be discovered for each of the different
diseases, it might be possible to target one or more steps in
each of the pathways.
Scientific Commentary
The distal myopathies and their relationship to the
mutated proteins that cause them remain fascinating. Other
distal myopathies are caused by mutations in the membrane
repair protein dysferlin (Liu et al., 1998) and the sialic acid
metabolism enzyme (GNE) (Kayashima et al., 2002), but
the fact remains that many distal myopathies are caused by
mutations in sarcomeric proteins. Interestingly, the gene for
Welander distal myopathy, the first definitive distal
myopathy described (Welander, 1951), has not yet been
found. It will be interesting to see which type of gene causes
Welander distal myopathy, with its phenotype so characteristically restricted to hand function. Right now, it
is hard to predict what type of mutation or gene that
might be.
Nigel G. Laing
Centre for Medical Research
University of Western Australia
Western Australian Institute for Medical Research
B Block
QEII Medical Centre
Nedlands
Western Australia 6009
Australia
E-mail: [email protected]
Advance Access publication April 30, 2007
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Scientific Commentary
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