476
chapter
21
Muscle and Nonmuscle Contractile Systems
21.4 Inherited Diseases of Muscle
Many disorders of skeletal and cardiac muscle due to ge-
netic defects have been described. Taken as a group, the
h y-
p ertro p h ic cardiom yopath ies
are the most common, with
a combined prevalence of about 1 in 500. By compari-
son, the most common muscular dystrophy,
Duchenne’s
muscular dystrophy
(DMD), has a prevalence of roughly
1 in 3500 male births. It is not known whether genetic de-
fects specific to myocardium are actually more common
than those affecting skeletal muscle, or whether cardiac
defects are simply more serious due to the incessant and
vital nature of cardiac work. Most of these genetic defects
do not affect both skeletal and cardiac muscle because
there are cardiac-specific forms of almost all sarcomeric
proteins and some enzymes. These disorders fall into the
following broad categories: cardiomyopathies, muscular
dystrophies, channelopathies (including the myotonias),
metabolic diseases, and mitochondrial gene defects (see
Chapter 14). The most prevalent examples of each are
summarized in Table 21-5.
Hypertrophic cardiomyopathy
(HCM) is a syndrome
characterized by dyspnea and chest pain associated with
decreased diastolic compliance and outflow obstruction
and left ventricular hypertrophy, usually without dilation.
More than 100 different mutations have been found in
HCM patients in genes coding for /1-MHC, essential and
regulatory MLC, Tn T, Tn I, a-tropomyosin, and myosin-
binding protein C. Most of these are transmitted as au-
tosomal dominant traits with variable penetrance. Those
cases due to defects in /f-MHC and Tn T are the most
severe and have the worst prognosis, and heavy chain mu-
tations are the most common type. About 15% of HCM is
due to mutations in chromosome
1 1
p
1 1
.
2
, which codes for
myosin-binding protein C, a structural protein that binds
myosin and titin, and may also play a role in mediating the
contractility response to adrenergic stimulation. Protein C
is 1274 amino acids long, and is coded for by a complex
gene comprising 24,000 base pairs in at least 37 exons.
D u ch en n e’s m u scu lar d ystroph y
(DMD), is a muscle
degenerative disease due to a recessive mutation in the
X chromosome. The mutation involves large defects in or
complete deletion of the gene coding for
dystrophin.
The
involved gene was identified by producing probes to the
DNA surrounding the site of a large deletion in the X chro-
mosome of a DMD patient. Applying these probes to the
DNA of normal individuals, it was possible to isolate DND
cDNA. Subsequent determination of the DNA sequence
made it possible to identify dystrophin (M.W. 426,000);
the gene coding dystrophin has over
2
million bases.
Dystrophin has
some similarities to
spectrin
and
lam inin,
which led to the realization that dystrophin is
involved in attaching the cytoskeleton to the extracellular
matrix (ECM). That is, dystrophin binds to webs of actin
filaments and to transmembrane glycoproteins which, in
turn, bind to ECM proteins such as laminin and agrin.
Dystrophin is required to transmit force from the my-
ofibrils through the costamere structure of the fiber to
the ECM, and ultimately, to the tendons of the muscle
(see subsection on
Myofibrils,
p. 457). Similarly, dys-
trophin allows forces applied to the sarcolemma via the
ECM to be transmitted to the myofibrils and be borne by
them rather than the sarcolemma, which cannot support
tension by itself. Lack of dystrophin results in mechan-
ical stresses in muscle tearing holes in the sarcolemma,
which causes sustained high [Ca2+]; and activation of
Ca-dependent proteases such as
calpains.
This leads to
focal destruction in the fiber, migration of polymorphonu-
clear leukocytes (PMNs) into the site, and either remod-
eling or total destruction of the fiber.
Becker’s muscular
dystrophy
(BMD) is allelic to DMD. Both DMD and BMD
patients often have defects or deletions of genes flanking
the dystrophin gene, and so present a varied clinical pic-
ture in which the muscular dystrophy is usually the most
prominent feature.
Channelopathies
are a varied group of rare hereditary
disorders due to defects, usually point mutations, in genes
for ion channel proteins. Most of these affect voltage-gated
channels. Two that do not are
Thomsen’s disease
(auto-
somal dominant myotonia congenita) and
Becker’s dis-
ease
(autosomal recessive generalized myotonia), which
are both due to mutations in a gene coding for a skeletal
muscle Cl- channel called C1C-1. Since Cl- conductance
stabilizes the membrane potential by allowing movement
of CL in response to depolarization, loss of 75% or more
of the CL conductance makes membranes unusually sus-
ceptible to the generation of action potentials by random
depolarizing stimuli and delays repolarization, resulting in
the unwanted twitches and contractions and difficulty in
releasing voluntary contractions seen in these disorders.
The channel is an oligomer, and some mutations in one
C1C-1 gene result in a protein that interacts negatively
with the normal (wild-type) peptide from the nonmutated
gene, suppressing its ion conductance. In such mutations,
association of a mutant channel with its normal allele pro-
duces a dysfunctional channel, so that only one mutated
gene is required to produce symptoms (Thomsen’s dis-
ease). Mutations that do not affect the properties of the
normal protein produce symptoms only in homozygous
individuals (Becker’s disease).
Most channelopathies have some features in common.
There are paroxysmal attacks of myotonia or paralysis,
migraine, or ataxia precipitated by physiological stressors.
They are often suppressed by membrane-stabilizing agents
