*160900 DYSTROPHIA MYOTONICA; DMPK
Alternative
titles; symbols
DYSTROPHIA MYOTONICA; DM
MYOTONIC DYSTROPHY
STEINERT DISEASE
DM-KINASE, INCLUDED; DMK, INCLUDED
DM PROTEIN KINASE, INCLUDED
MYOTONIN-PROTEIN KINASE, INCLUDED
MYOTONIC DYSTROPHY PROTEIN KINASE, INCLUDED; MDPK,
INCLUDED
table OF
CONTENTS
"173
MEDLINE Citations"
"29 Protein Links"
"29 Nucleotide Links"
"2 Genome Links" "Gene
Map" "GDB"
"Coriell
Cell Line Repository" "Nomenclature
Database"
Gene Map Locus: 19q13.2-q13.3
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TEXT
DESCRIPTION
- Myotonic dystrophy is an autosomal dominant
disorder characterized by myotonia, muscular
dystrophy, cataracts, hypogonadism, frontal
balding, and ECG changes. The discovery that the
genetic defect is an amplified trinucleotide
repeat in the 3-prime untranslated region of a
protein kinase gene on chromosome 19 explains
many of the unusual features of this disorder.
Severity varies with the number of repeats:
normal individuals have from 5 to 30 repeat
copies; mildly affected persons, from 50 to 80;
and severely affected individuals, 2,000 or more
copies. Amplification is frequently observed
after parent-to-child transmission, but extreme
amplifications are not transmitted through the
male line. This explains anticipation (increase
in severity in successive generations) and the
occurrence of the severe congenital form almost
exclusively in the offspring of affected women.
Rudnik-Schoneborn et
al. (1998) reviewed the obstetric histories
of 26 women with myotonic dystrophy who had a
total of 67 gestations, comparing gestations
with affected and unaffected fetuses. Of the 56
infants carried to term, 29 had or most likely
had inherited the gene for DM from their
affected mothers; 18 of the 29 (61%) were
affected by the congenital form of DM. Perinatal
loss rate was 11% and associated with congenital
DM. Preterm labor was a major problem in
gestations with DM-fetuses (55 vs 20%), as was
polyhydramnios (21% vs none). While forceps
deliveries or vacuum extractions were required
in 21% of deliveries with DM-fetuses and only 5%
of unaffected fetuses, the frequency of cesarean
sections were similar in the 2 groups. Obstetric
problems were inversely correlated with age at
onset of maternal DM, while no effect of age at
delivery or birth order on gestational outcome
was seen.
-
CLINICAL
FEATURES
-
ADULT-ONSET MYOTONIC
DYSTROPHY
-
GENERAL
The features are myotonia, muscle wasting and
weakness, cataract, hypogonadism, frontal
balding, and ECG changes. Typically, symptoms
become evident in middle life, but signs can be
detectable in the second decade. Bundey
et al. (1970) found that the most useful
method for identifying subclinical cases is
slit-lamp examination (for lens changes),
followed by electromyography (for myotonic
discharges), and then by measurement of
immunoglobulins
Caughey and
Myrianthopoulos (1963) provided a monograph
covering all aspects of myotonic dystrophy.
Caughey and
Myrianthopoulos (1991) privately published a
second edition. The frontispiece is a Greek
stamp commemorating Prince Ypsilante, a hero of
Greek liberation who, along with his brother,
was thought on good evidence to have had
myotonic dystrophy. Harper
(1989) provided a monograph on myotonic
dystrophy that has been updated
regularly
-
MUSCLE
Unlike the other muscular dystrophies, DM
initially involves the distal muscles of the
extremities and only later affects the proximal
musculature. In addition, there is early
involvement of the muscles of the head and neck.
Involvement of the extraocular muscles produces
ptosis, weakness of eyelid closure, and
limitation of extraocular movements. Atrophy of
masseters, sternocleidomastoids, and the
temporalis muscle produces a characteristic
haggard appearance. Bosma
and Brodie (1969) demonstrated both myotonia
and weakness in patients with swallowing and
speech disability. Myotonia, delayed muscular
relaxation following contraction, is most
frequently apparent in the tongue, forearm, and
hand. Myotonia is rarely as severe as in
myotonia congenita and tends to be less apparent
as weakness progresses
-
BIOPSY FEATURES
Many of the biopsy changes are nonspecific.
Most commonly there are central nuclei and ring
fibers. Necrosis, regeneration, and increase of
collagen are never as severe as in Duchenne
muscular dystrophy. In 70% of patients there is
hypotrophy of type I muscle fibers; less
commonly there are markedly atrophic fibers
(Casanova and Jerusalem,
1979). In many cases there are target
fibers, suggesting neurogenic dysfunction, but
intramuscular nerves appear histologically
normal (Drachman and
Fambrough, 1976). Ultrastructural studies
show dilatation of T tubules or sarcoplasmic
reticulum, whose contents may be unusually dense
(Fardeau et al.,
1965). In some cases the surface membrane
may be irregular, with reduplication of basal
lamina.
-
EYES
In studies of an extensively affected
Labrador kindred, Webb
et al. (1978) concluded that lens opacities
are not a reliable diagnostic sign. Many younger
affected persons, including one in his 20s, did
not have lens opacities despite clear muscular
involvement. On the other hand, Ashizawa
et al. (1992) concluded that bilateral
iridescent and posterior cortical lens opacities
are highly specific for DM and are useful for
establishing the clinical diagnosis. The
sensitivity of these 2 features was found to be
46.7% and 50.0%, respectively, in their series,
while their specificities were 100% in both
cases.
-
OTHER ORGANS
Diabetes mellitus occurs in 5% of cases,
frequently with hypersecretion of insulin
(Barbosa et al.,
1974). There is impaired responsiveness to
follicle stimulating hormone with hypogonadism
(Sagel et al.,
1975), often impairment of adrenal
androgens, and occasional thyroid dysfunction,
but pituitary function is usually intact
(Lee and Hughes,
1964). Di Chiro and
Caughey (1960) reviewed radiographic
findings in the skull in 18 cases. In 17,
'hyperostotic' changes in the vault were found,
the sex distribution being equal. In 8 cases
with hypogonadism, the hyperostosis was most
advanced.
Excessive catabolism of IgG contributes to
low circulating levels of IgG (Wochner
et al., 1966).
Hawley et al.
(1983) suggested that the tendency to have
heart block or arrhythmia with myotonic
dystrophy is a familial characteristic. The
implication was that there may be 2 forms of
myotonic dystrophy. They studied 18 families and
found heart block in 4.
Schwindt et al.
(1969) claimed that 25 to 50% of patients
have abdominal symptoms due to cholelithiasis.
Brunner et al. (1992)
described 4 DM patients with recurrent
intestinal pseudoobstruction. In 1 patient it
preceded significant muscle weakness by 15
years. Conservative measures usually were
effective. Improved intestinal function was
noted in 1 patient treated with the prokinetic
agent cisapride. A partial sigmoid resection was
performed in 3 patients with dolichomegacolon.
Two of the patients were sibs. Brunner
et al. (1992) pointed out that there are
many reports of familial occurrence of specific
complications of DM: cardiac conduction
disturbances, focal myocarditis, mitral valve
prolapse, pilomatrixomas, polyneuropathy, normal
pressure hydrocephalus, and dilatation of the
urinary tract. (Familial idiopathic intestinal
pseudoobstruction occurs as an intestinal
myopathy (155310)
or in a neuronal form (243180).)
It occurs also in Duchenne muscular dystrophy
(310200).
From a series of neurophysiologic
investigations of 24 patients with myotonic
dystrophy, Jamal et al.
(1986) concluded that there was unequivocal
evidence of widespread nervous system
dysfunction. In many patients there was
significant involvement of peripheral large
diameter motor and sensory fibers and of small
diameter sensory fibers peripherally and/or
centrally. The authors stated that 'the concept
of myotonic dystrophy as a pure myopathy can no
longer be sustained.' This conclusion is
supported by the findings in the family reported
by Spaans et al.
(1986). Thirteen members of a large family
presented with a hereditary motor and sensory
neuropathy in a dominant pedigree pattern. The
mean motor conduction velocities for the median
and peroneal nerves in the affected individuals
were 62% and 56%, respectively, of those of the
unaffected relatives. Eight of the 13 affected
members also showed more or less prominent signs
of myotonic dystrophy. There was no case of
myotonic dystrophy alone.
Turnpenny et al.
(1994) found that IQ in myotonic dystrophy
declined as the age of onset of signs and
symptoms decreased and as the size of the CTG
expansion increased. The correlation appeared to
be more linear with age of onset. Censori
et al. (1994) carried out a prospective
case-control study of 25 patients with myotonic
dystrophy using magnetic resonance imaging (MRI)
of the brain. They found that 84% of myotonic
dystrophy patients showed white matter
hyperintense lesions, compared with 16% of
controls. Most of these lesions involved all
cerebral lobes without hemispheric prevalence,
but 28% of the myotonic dystrophy patients also
showed particular white matter hyperintense
lesions at their temporal poles. Myotonic
patients also showed significantly more cortical
atrophy than did controls. However, there was no
relationship between atrophy or white matter
hyperintense lesions and age, disease duration,
or neuropsychologic impairment. Damian
et al. (1994) found that amplification of
the CTG repeat in leukocytes strongly correlated
with cognitive test deficits when the expansion
length exceeded over 1,000 trinucleotides. MRI
lesions were associated with impaired
psychometric performance, but the MRI findings
of subcortical white matter lesions correlated
only very weakly with the molecular findings.
In a single large kindred, Tokgozoglu
et al. (1995) compared the cardiac findings
in 25 patients with myotonic dystrophy with
age-matched normal family members. They found
that the patients were more likely to have
conduction abnormality (52% vs 9%), mitral valve
prolapse (32% vs 9%), and wall motion
abnormality (25% vs 0%). Left ventricular
ejection fractions and stroke volume were
reduced compared with normals. Using
multivariate analysis, the number of CTG repeats
(range, 69 to 1367; normal, less than 38) was
the strongest predictor of abnormalities in wall
motion and EKG conduction. Patients with more
extensive neurologic findings had a higher
incidence of wall motion and/or EKG conduction
abnormalities. The authors also found that the
relation of mitral valve prolapse to the size of
the CTG repeat was of borderline significance.
-
CONGENITAL MYOTONIC DYSTROPHY
Harper (1975)
observed that in a small proportion of cases,
myotonic dystrophy may be congenital with
neonatal hypotonia, motor and mental
retardation, and facial diplegia. With rare
exception, it is the mother who transmits the
disease. Diagnosis can be difficult if the
family history is not known because muscle
wasting may not be apparent, and cataracts and
clinical myotonia are absent, although the
latter is sometimes detectable by
electromyography. Fried
et al. (1975) observed that infants with
neonatal myotonic dystrophy (almost always the
mother is affected) have thin ribs. Talipes at
birth, together with hydramnios and reduced
fetal movements during pregnancy, is frequent.
Respiratory difficulties are frequent and are
often fatal. Those that survive the neonatal
period initially follow a static course,
eventually learning to walk but with significant
mental retardation in 60 to 70% of cases. By age
10 they develop myotonia and in adulthood
develop the additional complications described
for the adult-onset disease. Roig
et al. (1994) reported long-term follow-up
of 18 patients diagnosed with congenital
myotonic dystrophy. Three of the 18 had died,
and 5 were lost to follow-up. The remaining 10
had IQs of less than 65. Universal findings were
language delay, hypotonia, and delayed motor
development. There was no difficulty with
routine immunizations nor were there anesthetic
complications observed in any of the 7 patients
who underwent surgery.
-
OTHER
FEATURES
- In the cytoplasm of cultured skin
fibroblasts Swift and
Finegold (1969) found an abnormally large
amount of material with the staining properties
of acid mucopolysaccharides. Because of the
similarity of platelet actomyosin
('thrombosthenin') to that of muscle, Bousser
et al. (1975) studied platelets in myotonic
dystrophy. Although they found a normal pattern
of aggregation in response to adenosine
diphosphate and collagen, aggregation occurred
with exceedingly low levels of adrenalin. A
growing body of evidence was interpreted as
indicating a generalized defect of cell
membranes in myotonic dystrophy (Butterfield
et al., 1974; Roses
et al., 1975).
Using antisera developed against synthetic
DM-PK peptide antigens for biochemical and
histochemical studies, van
der Ven et al. (1993) found lower levels of
immunoreactive DM-kinase protein of 53 kD in
skeletal and cardiac muscle extracts of DM
patients than in normal controls.
Immunohistochemical staining revealed that DM-PK
is localized predominantly at sites of
neuromuscular and myotendinous junctions of
human and rodent skeletal muscles. The protein
could also be demonstrated in the neuromuscular
junctions of muscular tissues of adult and
congenital cases of DM, with no gross changes in
structural organization.
-
INHERITANCE
- This disorder segregates as an autosomal
dominant with greatly variable penetrance. Many
obligatory gene carriers are asymptomatic. With
only rare exception, it is the mother who
transmits the disease in cases of congenital
myotonic dystrophy. Patients born of affected
mothers are more severely affected than those
born of affected fathers (Harper
and Dyken, 1972). In Japan, Tanaka
et al. (1981) also noted the maternal effect
in age of onset and severity, and thought that a
chemical factor, deoxycholic acid, is
responsible for the effect.
Ott et al. (1990)
described DNA marker-based genetic counseling in
a family with an affected mother and 3 children,
each by a different partner. Two of the children
were affected. In the third child, myotonic
dystrophy could be excluded in the
presymptomatic period. In genetic counseling,
the recommended risk estimate that any
heterozygous woman with myotonic dystrophy will
have a congenitally affected child is 3 to 9%.
However, after having such an offspring, a DM
mother's risk increases to 20 to 37% (Koch
et al., 1991). Koch
et al. (1991) concluded that the clinical
status of the mother at the time of pregnancy
and delivery had an important influence on the
outcome in the infant. Only women with
multisystem effects of the disorder had a
congenitally affected child. No heterozygous
woman with polychromatic lens changes as the
only finding had a congenitally affected child.
For classically affected women with systemic
manifestations, risk figures that approach the
occurrence risk given to mothers with previously
born congenitally affected children seemed
appropriate. The findings of this study
supported the earlier proposal that maternal
metabolites acting on a heterozygous offspring
account for the congenital involvement. Neither
genomic imprinting nor mitochondrial inheritance
could explain the correlation between the
clinical status of heterozygous mothers and that
of their children.
Contrary to the findings and conclusions of
Koch et al. (1991),
Goodship et al.
(1992) described a family in which a
53-year-old woman had no symptoms of myotonic
dystrophy, a normal electromyogram, and only dot
polychromatic lens opacities on slit-lamp
examination. She had, however, given birth 30
years before to a child with congenital myotonic
dystrophy. Furthermore, she had a son and
daughter with adult onset of symptoms of
myotonic dystrophy and another daughter who
after normal developmental milestones had early
adult onset of symptoms and who gave birth to an
offspring with congenital myotonic dystrophy.
Ives et al. (1989)
described possible homozygosity for the DM gene.
The possible homozygotes were more severely
affected than heterozygotes. For a variety of
reasons the authors had found it difficult to
obtain molecular proof of homozygosity. On the
other hand, Cobo et al.
(1993) studied a consanguineous
French-Canadian family in which 2 sisters were
homozygous for the 'at risk' haplotype but were
asymptomatic and showed no evidence of DM on
extensive clinical examination. Both sisters
possessed 2 alleles with repeat sizes normally
seen in minimally affected patients. Both
parents were affected. Martorell
et al. (1996) described 3 unrelated
homozygous myotonic dystrophy patients. One
patient had the classic form of myotonic
dystrophy and the other 2 were mildly affected.
A remarkable feature was the mildness of the
phenotype in the homozygous patients; one, for
example, had late-onset cataract as the only
manifestation. With the observations of
Cobo et al. (1993),
this led Zlotogora
(1997) to conclude that in myotonic
dystrophy, homozygotes do not differ from
heterozygotes and that, like Huntington disease
(HD; 143100),
DM is a 'true dominant.'
On the possibility that mitochondrial genetic
modifying factors might be responsible for DM,
Thyagarajan et al.
(1991) completely sequenced the
mitochondrial genome in 2 patients with
congenital DM. Comparison of the 2 sequences
with control data failed to reveal any specific
nucleotide or length variant. After isolation of
the gene mutant in myotonic dystrophy and
identification of its gene product as a
serine-threonine kinase, Jansen
et al. (1993) tested for evidence of
imprinting of either the paternal or the
maternal alleles in both human and mouse
tissues. No evidence of imprinting was found
involving the expression of the DM kinase
gene.
Jansen et al.
(1994) used the term gonosomal mosaicism to
refer to combined somatic and germline mosaicism
which they demonstrated in DM. Studies of
variation in the (CTG)n repeat in sperm and body
cells of the same individual were demonstrated.
The rather frequent observation of offspring
with triplet repeat length larger than that
found in sperm suggested that intergenerational
length changes in the unstable (CTG)n repeat
occur during early embryonic mitotic divisions.
The initial size of the (CTG)n repeat, the
overall number of cell divisions involved in
tissue formation, and a specific selection
process in spermatogenesis may all influence
variation in repeat size.
Carey et al.
(1994) examined meiotic drive and
segregation distortion at the DM locus. The
study was undertaken because the haplotype
analysis of DM chromosomes had detected a very
limited pool of founder chromosomes (Harley
et al., 1992; Mahadevan
et al., 1992), raising the question of how a
disease that usually decreases reproductive
fitness within a few generations has been
maintained in the population over hundreds of
generations. Carey et al.
(1994) found that healthy individuals
heterozygous for DM alleles in the normal size
range preferentially passed on alleles of more
than 19 CTG repeats to their offspring. They
suggested that this phenomenon may act to
replenish a reservoir of potential DM mutations
and that this distortion of the transmission
ratio may offer an example of meiotic drive in
humans. This segregation distortion may act as a
mechanism to maintain alleles in the population
that lie at the larger end of the normal range
in the trinucleotide repeat disorders. It was
unclear whether the segregation distortion was a
direct consequence of the CTG repeat number or
whether the preferential transmission of the
larger allele was due to linkage to segregation
distorting loci on the same chromosome.
Leeflang et al.
(1996) directly analyzed meiotic segregation
and the question of meiotic drive at the DM
locus using single-sperm typing. They studied
samples of single sperm from 3 individuals
heterozygous at the DM locus, each with one
allele larger and one allele smaller than the 19
CTG repeats. To guard against the possible
problem of differential PCR amplification rates
based on the lengths of the alleles, the sperm
were also typed at another closely linked marker
whose allele size was unrelated to the allele
size of the DM locus: D19S207 in 2 donors and
D19S112 in the third. Using statistical models
specifically designed to study single-sperm
segregation data, they found no evidence of
meiotic segregation distortion. This suggested
to Leeflang et al.
(1996) that any greater amount of
segregation distortion at the DM locus must
result from events following sperm ejaculation.
Magee and Hughes
(1998) studied 44 sibships with myotonic
dystrophy. When the transmitting parent was
male, 58.3% of the offspring were affected, and
when the transmitting parent was female, 68.7%
were affected. Overall, the DM expansion was
transmitted in 63% of cases. Magee
and Hughes (1998) concluded that DM
expansion tends to be transmitted
preferentially.
Nakagawa et al.
(1994) described 2 sisters with congenital
myotonic dystrophy born to a normal mother and
an affected father. The sisters had symptoms
from birth. The age of onset of DM in the father
was 39 years. Analysis of the CTG trinucleotide
expansion in this family showed increase in the
repeat length with increasing severity, with the
smallest expansion in the grandfather and the
largest expansion in the younger of the 2
affected sisters. The observation refutes the
hypothesis that congenital DM is exclusively of
maternal origin.
Bergoffen et al.
(1994) observed inheritance from a mildly
affected father. This family illustrated that
the congenital form can occur without
intrauterine or other maternal factors
operating. Nakagawa et
al. (1993) also reported a case of
congenital myotonic dystrophy inherited from the
father. De Die-Smulders
et al. (1997) reported a further case of
congenital myotonic dystrophy inherited from the
father. The patient was a 23-year-old, mentally
retarded male suffering from severe muscular
weakness who presented with respiratory and
feeding difficulties at birth. His 2 sibs
suffered from childhood-onset DM, whereas their
father had adult onset of DM at around 30 years
of age. De Die-Smulders
et al. (1997) reviewed 6 other cases of
paternal transmission of congenital DM and found
that the fathers of these children showed, on
average, shorter CTG repeats and hence less
severe clinical symptoms than the mothers of
children with congenital DM. The authors
concluded that paternal transmission of
congenital DM preferentially occurs with onset
of DM past 30 years of age in the father.
In a study of mitochondrial DNA from 35
patients with congenital myotonic dystrophy,
Poulton et al.
(1995) could find no evidence that mutations
in mtDNA are involved in the pathogenesis of
congenital myotonic dystrophy. Associated
mitochondrial mutations might help account for
the maternal inheritance pattern and the early
onset of the congenital form.
-
CYTOGENETICS
- Fryns et al.
(1984) reported the case of a 21-year-old
woman with myotonic dystrophy and a balanced
translocation t(2;20)(p21;q11), both occurring
de novo. An incorrect identification of
chromosome 19 as chromosome 20 was excluded by
banding studies. This is probably an indication
of incorrect assignment on the basis of balanced
translocation. The association of mendelian
disorders with seemingly balanced translocations
has been a useful method of tentative
chromosomal assignment of the locus involved in
the disease mutation. Examples of disorders
mapped in this way are Duchenne muscular
dystrophy (310200),
several other X-linked conditions (304050,
305400,
307600,
309900),
and, less securely established, the autosomal
disorders spherocytosis (182900)
and anterior polar cataract (115650).
(Balanced translocations, either familial or
acquired, underlie malignancies, e.g., renal
cell carcinoma and various hematologic
malignancies, notably chronic myeloid leukemia
and Burkitt lymphoma. In some of these cases,
position effect may be the mechanism rather than
damage of a locus through interruption by a
breakpoint.)
-
MAPPING
- The linkage of secretor (Se; 182100)
and myotonic dystrophy was suspected by
Mohr (1954) when he
was doing the studies that demonstrated the
first autosomal linkage in humans, that between
secretor and Lutheran blood group (Lu; 111200).
Mohr (1954) failed
to establish fully the DM linkage because of the
relative insensitivity of the sib-pair method of
linkage analysis he was using (Smith,
1986). Renwick et
al. (1971) confirmed the linkage. The
Lu-Se-DM linkage group and the Km (Inv)-Jk-Co
linkage group were tentatively tied together by
a family with myotonic dystrophy reported by
Larsen et al. (1979,
1980). From study of
a single large kindred, Larsen
et al. (1979) suggested that Km and Jk are
linked to myotonic dystrophy. An order of Km,
Jk, Lu, Se, and DM was suggested. No
recombination in 7 informative meioses occurred
between Km and Jk, none in 5 between Se and DM,
3 out of 10 between Jk and Se, and 3 in 12
between Jk and DM.
Eiberg et al. (1981,
1983) concluded that
C3 (120700),
Le (111100),
myotonic dystrophy, secretor, and Lutheran are
linked. Since fibroblast C3 had been assigned to
chromosome 19, the finding indicated that
myotonic dystrophy is on chromosome 19,
providing serum C3 (polymorphism of which was
used in the above linkage studies) is under the
same genetic control (or at least syntenic
genetic control) as fibroblast C3.
Cook (1981) had
found positive lod scores for serum C3 and
peptidase D (170100),
a chromosome 19 locus. Linkage of peptidase D to
myotonic dystrophy (O'Brien
et al., 1983) proved the assignment of the
Lutheran-secretor linkage group to chromosome 19
and provided regional assignment. Using an RFLP
related to a C3 probe, Davies
et al. (1983) found evidence of linkage with
myotonic dystrophy. Laberge
et al. (1985) found a lod score of 4.574 at
a recombination fraction of 0.12 for linkage of
DM and APOE (107741)
in French Canadians (males and females
combined). Meredith et
al. (1985) found close linkage (maximum lod
= 7.8 at 4% recombination) of DM to APOC2
(207750).
APOE and APOC2 are known to be closely linked.
Brook et al.
(1985) concluded that the DM locus is
probably in the 19p13.2-19cen segment. Friedrich
et al. (1987) quoted studies of somatic cell
hybrids carrying various fragments of chromosome
19 that provide unambiguous proof for location
of the PEPD gene on 19q, thus corroborating the
assignment of DM to that region. The hereditary
motor and sensory neuropathy in the family
described by Jamal et al.
(1986) showed segregation with genetic
markers known to be linked to myotonic dystrophy
on chromosome 19. Spaans
et al. (1986) raised the question of whether
the disorder might be caused by an allele of the
'common' DM gene or alternatively by 2 closely
linked genes on chromosome 19.
Shaw et al.
(1986) reviewed gene mapping of chromosome
19 with particular reference to myotonic
dystrophy. Suppression of recombination near the
centromere and the large male-female differences
in recombination are 'complications' of linkage
mapping of the DM locus and use of linkage
markers in genetic counseling. Shaw
et al. (1986) concluded from linkage studies
that myotonic dystrophy is located in the region
of the centromere of chromosome 19.
Roses et al.
(1986) described RFLPs at the D19S19 locus,
which is linked to DM (maximum lod = 11.04 at
theta = 0.0). Bartlett et
al. (1987) reported that the genomic clone
called LDR152 (D19S19) is tightly linked to DM;
the maximum lod score was 15.4 at a
recombination fraction = 0.0 (95% confidence
limits 0.0-0.03). Using 2 RFLPs of the APOC2
gene, Pericak-Vance et
al. (1986) demonstrated tight linkage to
myotonic dystrophy; the maximum lod score was
16.29 at a recombination fraction of 0.02.
In 3 large kindreds, Friedrich
et al. (1987) did linkage studies using
RFLPs related to the C3 gene and the chromosome
19 centromeric heteromorphism as genetic
markers. Three-point linkage analysis excluded
DM from the 19cen-C3 segment and strongly
supported its assignment to the proximal long
arm of chromosome 19.
Harper (1986)
demonstrated 2 to 5% recombination between
myotonic dystrophy and APOC2, leading him to the
conclusion that myotonic dystrophy may be just
onto 19q or very close to the centromere on 19p.
Bird et al. (1987)
concluded that the APOC2 gene is very closely
linked to the DM locus and proposed that APOC2
markers may be used for prenatal diagnosis of
myotonic dystrophy because the loci are closely
linked. Smeets et al.
(1988) used synthetic oligonucleotides to
discriminate between E3 and E4 alleles of APOE.
The relevant segment of the APOE gene was
enzymatically amplified and linkage with DM
tested. A maximum lod score of 7.47 at a
recombination frequency of 0.047 was found (male
theta = female theta). No recombination (maximum
lod score = 5.61 at theta = 0.0) was found
between APOE and APOC2. Further analysis of the
relationship of the human APOC2 gene to myotonic
dystrophy was provided by MacKenzie
et al. (1989), who reported a linkage study
utilizing 6 RFLPs in 50 families with myotonic
dystrophy. They observed significant linkage
disequilibrium between the DM locus and APOC2
alleles. The maximum lod score was 17.869 at a
theta of 0.04.
Bender et al.
(1989) found no evidence of linkage with any
of 35 serologic and biochemical markers.
Brunner et al. (1989)
concluded that the DM and CKMM loci are distal
to the APOC2-APOE gene cluster; the orientation
of DM and muscle-type creatine kinase (CKMM;
123310)
was undetermined.
Johnson et al.
(1989) presented evidence that DM is distal
to the apolipoprotein cluster. Yamaoka
et al. (1990) found a maximum lod score of
28.41 at theta = 0.01 for the linkage between
CKMM and DM. They concluded, furthermore, that
CKMM is on the same side and closer to DM than
APOC2. Walsh et al.
(1990) found a peak lod score of 9.29 at 2
cM for linkage of DM to APOC1 (107710)
and a lod score of 8.55 at 4 cM for linkage of
DM to CYP2A (123960).
A maximum lod score of 9.09 at theta = 0.05 was
observed for the linkage of APOC1 to CYP2A.
CYP2A appeared to be proximal to DM, CKMM, and
APOC2.
Smeets et al.
(1989), Davies et al.
(1989), Roses et al.
(1989), Brunner et
al. (1989), Harley et
al. (1989), Brook et
al. (1989), and Miki
et al. (1989) presented linkage data for
markers surrounding the myotonic dystrophy locus
on human chromosome 19. Smeets
et al. (1989) and Davies
et al. (1989) also presented physical maps
of the region derived from pulsed field gel
electrophoresis analysis.
In a study of 65 myotonic dystrophy families
from Canada and The Netherlands, Brunner
et al. (1989) obtained a maximum lod score
of 22.8 at a recombination frequency of 0.03 for
linkage to CKMM. Bailly et
al. (1991) excluded mutation of the CKMM
gene as the cause of this disorder. CKMM cDNA
was isolated from the skeletal muscle of an
individual with DM. Sequencing of the CKMM cDNA
from the chromosome 19 carrying the DM gene
showed 2 novel polymorphisms but no
translationally significant mutation.
Harley et al.
(1991) concluded that the DM gene lies in
region 19q13.2-q13.3 and that the closest
proximal markers are APOC2 and CKM,
approximately 3 cM and 2 cM from DM,
respectively, in the order cen--APOC2--CKMM--DM.
Ten of 12 polymorphic markers on 19q were shown
to be proximal to the DM gene; the 2 that were
distal to DM, PRKCG (176980)
and D19S22, were approximately 25 cM and 15 cM,
respectively, removed from DM.
Brunner et al.
(1991) restudied the family reported by
Spaans et al.
(1986), ruled out linkage to chromosome 17
markers, thus excluding the gene (601097)
associated with Charcot-Marie-Tooth disease,
type Ia (118220),
and demonstrated linkage to DNA markers from the
APOC2 locus on chromosome 19. All affected
individuals had inherited a unique APOC2
haplotype that was not found in their clinically
and electrophysiologically normal sibs. In this
family, a moderately severe neuropathy appeared
to be the only clinical sign of myotonic
dystrophy for many years. The results were
consistent with either an unusual neuropathic
mutation in the DM gene or involvement of 2
closely linked genes.
Linkage studies by Cobo
et al. (1992) established the D19S63 marker
as useful for prenatal and presymptomatic
diagnosis and, as the closest marker to DM, in
isolating the gene.
-
MOLECULAR
GENETICS
-
-
IDENTIFICATION OF AN EXPANDED TRIPLET
REPEAT
Harley et al.
(1992) isolated a human genomic clone that
detected novel restriction fragments specific to
persons with myotonic dystrophy. A 2-allele
EcoRI polymorphism was seen in normal persons,
but in most affected individuals one of the
normal alleles was replaced by a larger
fragment, which varied in length both between
unrelated affected individuals and within
families. The unstable nature of this region was
thought to explain the characteristic variation
in severity and age at onset of the disease.
From a region of chromosome 19 flanked by 2
tightly linked markers, ERCC1 (126380)
proximally and D19S51 distally, Buxton
et al. (1992) isolated an expressed sequence
that detected a DNA fragment that was larger in
affected persons than in normal sibs or
unaffected controls.
Aslanidis et al.
(1992) cloned the essential region between
the above mentioned markers in a 700-kb contig
formed by overlapping cosmids and yeast
artificial chromosomes (YACs). The central part
of the contig bridged an area of about 350 kb
between 2 flanking crossover borders. This
segment, which presumably contained the DM gene,
was extensively characterized. Two genomic
probes and 2 homologous cDNA probes were
situated within approximately 10 kb of genomic
DNA and detected an unstable genomic segment in
myotonic dystrophy patients. The length
variation in this segment showed similarities to
the instability seen in the fragile X locus
(309550).
The authors proposed that the length variation
was compatible with a direct role in the
pathogenesis of myotonic dystrophy.
Using positional cloning strategies,
Brook et al. (1992)
identified a CTG triplet repeat that is larger
in myotonic dystrophy patients than in
unaffected individuals. This sequence is highly
variable in the normal population. Unaffected
individuals have between 5 and 27 copies.
Myotonic dystrophy patients who are minimally
affected have at least 50 repeats, while more
severely affected patients have expansion of the
repeat-containing segment up to several kilobase
pairs.
Tsilfidis et al.
(1992) found a correlation between the
length of the CTG trinucleotide repeat and the
occurrence of severe congenital myotonic
dystrophy. Furthermore, mothers of congenital DM
individuals had higher than average CTG repeat
lengths.
Thornton et al.
(1994) reported the clinical findings,
muscle pathology, and genetic data on 3
individuals from 2 families with myotonic
dystrophy in whom no trinucleotide repeat
expansion was detected. The diagnosis of DM was
based on involvement of the lens, cardiac
conduction system, skin, and testes, in
association with muscle weakness and myotonia.
The diagnosis was supported by an autosomal
dominant pedigree pattern and by features of
muscle histopathology consistent with DM. This
may be a situation like that of the fragile X
syndrome in which rare affected individuals lack
a trinucleotide repeat expansion and instead
have deletions or point mutations.
Martorell et al.
(1995) determined the CTG repeat length in
23 DM patients with varying clinical severity
and various sizes of repeat amplification. They
confirmed the findings of previous studies that
there was no strong correlation between repeat
length and clinical symptoms but found that the
repeat length in peripheral blood cells of
patients increased over a 5-year period,
indicating continuing mitotic instability of the
repeat throughout life. The degree of expansion
correlated with the initial repeat size, and 50%
of the patients with continuing expansion showed
clinical progression of their disease symptoms
over the 5-year study period.
-
ANTICIPATION
Buxton et al.
(1992) found that the size of the fragment
varied between affected sibs and also increased
through generations in parallel with increasing
severity of the disease. They reported a family
in which persons in the first 2 generations had
mild symptoms and a CTG repeat unit of
approximately 60 repeats, whereas persons in the
third and fourth generations had severe symptoms
and a dramatic expansion in allele size--a
demonstration of the physical basis of
anticipation in myotonic dystrophy. Mahadevan
et al. (1992) found an expansion of the CTG
repeat region in the 3-prime untranslated region
of the DM candidate gene in 253 of 258 (98%)
persons with DM. They likewise observed that an
increase in the severity of the disease in
successive generations was accompanied by an
increase in the number of trinucleotide repeats.
Thus, 'anticipation' (progressively earlier
onset and greater severity of symptoms), long a
puzzling feature of DM, has an explanation and
physical documentation in the progressive
'worsening' of the mutation. Buxton
et al. (1992) postulated that this
represented an unstable DNA sequence responsible
for DM.
Tsilfidis et al.
(1992) also examined the amount of
intergenerational amplification in DM
mother/offspring pairs. The average increase in
the pairs with congenital DM was not
statistically greater than that shown by
noncongenital DM pairs. It was noteworthy,
however, that whereas 9 of 42 cases (21%) showed
no intergenerational amplification between
mother and noncongenital offspring, all
mother/congenital offspring pairs showed
intergenerational amplification. In another
analysis, they found that the intergenerational
CTG repeat length increase was the same whether
the father or the mother contributed the DM
allele to the offspring.
Fu et al. (1992)
reported that in the case of severe congenital
DM, the paternal triplet repeat allele was
inherited unaltered, while the maternal,
DM-associated allele was unstable. They
suggested that the mutational mechanism leading
to DM is triplet repeat amplification, similar
to that occurring in the fragile X syndrome. The
genomic repeat is p(AGC)n. Richards
and Sutherland (1992), therefore, referred
to the trinucleotide repeat as p(AGC)n/p(CTG)n.
They pointed out that this is the same repeat
sequence found in the androgen receptor gene
(313700)
and amplified in Kennedy disease (313200),
although transcription in the latter disorder is
from the opposite strand of DNA. Richards
and Sutherland (1992) indicated that the
instability of the DM element extends beyond
meiotic instability in affected pedigrees to
mitotic instability, manifest as somatic
variation--a smear of bands evident in some
affected persons. Progression of somatic CTG
repeat length heterogeneity in the blood cells
of myotonic dystrophy patients was documented by
Martorell et al.
(1998). They studied repeat length changes
over time intervals of 1 to 7 years in 111
myotonic dystrophy patients with varying
clinical severity and CTG repeat sizes. There
was a correlation between the progression of
size heterogeneity over time and the initial CTG
repeat size.
The expansion of a CTG trinucleotide repeat,
which represents the myotonic dystrophy
mutation, is in complete linkage disequilibrium
in both Caucasian (Harley
et al., 1991) and Japanese (Yamagata
et al., 1992) patients with a 2-allele
insertion/deletion polymorphism located 5 kb
upstream from the repeat, suggesting a single
origin of the mutation. This finding was
unexpected for a dominant disease that in its
severe form diminishes or abolishes reproductive
fitness. Such diseases are usually characterized
by a high level of new mutations that compensate
for the loss of abnormal alleles due to the
decreased fitness. It was therefore suggested
that DM could be due to recurrent mutations
occurring on the background of a predisposing
allelic form of the normal gene. Imbert
et al. (1993) studied the association of CTG
repeat alleles in a normal population to alleles
of the insertion/deletion polymorphism and of a
(CA)n repeat marker 90 kb from the DM mutation.
The results strongly suggested that the initial
predisposing event(s) consisted of a transition
from a (CTG)-5 allele to an allele with 19 to 30
repeats. The heterogenous class of (CTG)-19-30
alleles, which was found to have an overall
frequency of about 10%, may constitute a
reservoir for recurrent DM mutations.
Krahe et al.
(1995) reported results in a Nigerian
(Yoruba) DM family, the only indigenous
sub-Saharan DM case reported to that time, that
caused them to reassess the hypotheses that (1)
the predisposition for (CTG)n instability
resulted from a founder effect that occurred
only once or a few times in human evolution; and
(2) elements within the disease haplotype may
predispose the (CTG)n repeat to instability. (A
single haplotype composed of 9 alleles within
and flanking the DM locus over a physical
distance of 30 kb had been shown to be in
complete linkage disequilibrium with DM.) All
affected members of the Nigerian family had an
expanded (CTG)n repeat in one allele of the DM
gene. However, unlike all other DM populations
studied to that time, disassociation of the
(CTG)n repeat expansion from other alleles of
the putative predisposing haplotype was found.
Krahe et al. (1995)
concluded that in this family, the expanded
(CTG)n repeat was the result of an independent
mutational event. This weakens the hypothesis
that a single ancestral haplotype predisposes to
repeat expansion.
Yamagata et al.
(1996) studied linkage disequilibrium
between CTG repeats and an Alu
insertion/deletion polymorphism in the DMPK gene
in 102 Japanese families, of which 93 were
affected with DM. All of the affected
chromosomes were in complete linkage
disequilibrium with the Alu insertion allele. A
strikingly similar pattern of linkage
disequilibrium observed in European populations
suggested a common origin of the DM mutation in
the Japanese and European populations. The
authors speculated that this mutation arose in a
common Eurasian ancestor after the first
separation of the African and the non-African
populations, in light of the fact that the
family reported by Krahe
et al. (1995) did not show linkage
disequilibrium with the Alu insertion/deletion
polymorphism. Presumably, the mutation in that
family represented a less-ancient event than the
Eurasian mutation, accounting for the fact that
DM is extremely rare in African populations.
Harley et al.
(1993) demonstrated in 439 individuals
affected with myotonic dystrophy from 101
kindreds that the size of the unstable CTG
repeat detected in nearly all cases was related
both to age at onset of the disorder and to the
severity of the phenotype. The largest repeat
sizes, 1.5 to 6.0 kb, were seen in patients with
congenital myotonic dystrophy, while the
minimally affected patients had repeat sizes of
less than 0.5 kb. Only 4 of 182 parent-child
pairs showed a definite decrease in repeat size
in the offspring; almost all showed that the
offspring had an earlier age of onset and a
larger repeat size than their parents. Increase
in repeat size from parent to child was similar
for both paternal and maternal transmissions
when the increase was expressed as a proportion
of the parental repeat size. Analysis of
congenitally affected cases showed not only that
they had on the average the largest repeat
sizes, but also that their mothers had larger
mean repeat sizes, supporting previous
suggestions that a maternal effect is involved.
Brunner et al.
(1993) examined the kinetics of triplet
expansion by analyzing repeat length in
offspring of 38 carriers with small mutations
(less than 100 CTG trinucleotides). Repeat
lengths greater than 100 were more common in
offspring of male transmitters than in offspring
of female transmitters. They suggested that
selection against sperm with extreme
amplifications may be required to explain
maternal inheritance of congenital myotonic
dystrophy.
Sutherland and
Richards (1992) editorialized on the
legitimization of anticipation. According to
Harper et al. (1992),
'The history of the scientific study of
anticipation is...to a remarkable degree, the
history of myotonic dystrophy.' In the second
decade of this century, several observers
noticed that ancestors of myotonic dystrophy
patients had cataracts but no muscular symptoms
themselves.
Brunner et al.
(1993) and others observed the opposite of
anticipation, namely, reverse mutation. They
observed 2 families in which an affected father
transmitted a normal allele to an offspring; in
each case, an expanded CTG trinucleotide repeat
decreased in size to the normal range. This was
the first report of spontaneous correction of a
deleterious mutation upon transmission to
unaffected offspring in humans. Abeliovich
et al. (1993) likewise observed what they
referred to as 'negative expansion': a family in
which the affected father had a 3.0-kb expansion
of the DM unstable region, and a fetus inherited
the mutated gene but with an expansion of only
0.5 kb. See review by Brook
(1993). Ashizawa et
al. (1994), who referred to the phenomenon
as contraction rather than negative expansion,
showed that it occurred in 6.4% of 1,489 DM
offspring. Approximately one-half of these cases
showed clinical anticipation despite the reduced
CTG repeat size in the offspring. The most
striking examples were 2 cases in which
anticipation resulted in congenital DM in the
offspring with contractions of the CTG repeat.
They did not observe a single case in which the
age at onset of DM in the symptomatic offspring
was later than the age at onset in the parent,
although Harley et al.
(1993) reported 3 such cases.
Lavedan et al.
(1993) found differently sized repeats in
various DM tissues from the same individual,
which may explain why the size of the mutation
observed in lymphocytes does not necessarily
correlate with the severity and nature of
symptoms. With CTG sequences of more than 0.5
kb, Lavedan et al.
(1993) observed that intergenerational
variation was greater through female meioses,
whereas a tendency to compression was observed
almost exclusively in male meioses. For CTG
sequences under 0.5 kb, a positive correlation
was observed between the size of the repeat and
the intergenerational enlargement for both male
and female meioses. Anvret
et al. (1993) found in 8 patients with
myotonic dystrophy that the length of the CTG
repeat expansion was greater in DNA isolated
from muscle than in DNA isolated from
lymphocytes. Dubel et al.
(1992) found heterogeneity in the size of
amplification in affected identical twins.
A family with myotonic dystrophy described by
de Jong (1955) was
restudied by de
Die-Smulders et al. (1994) from the point of
view of the long-term effects of anticipation.
They defined clinical anticipation as the
cascade of mild, adult, childhood, or congenital
disease in successive generations. Such clinical
anticipation appeared to be a relentless process
occurring in all affected branches of the
5-generation family studied. The transition from
the mild to the adult type was associated with
transmission through a male parent. Stable
transmission of the asymptomatic/mild phenotype
showed a female transmission bias. Gene loss in
the patients in this family was complete, owing
to infertility of the male patients with
adult-onset disease and the fact that mentally
retarded patients did not procreate. Of the 46
at-risk subjects in the 2 youngest generations,
only 1 was found to have a full mutation. This
is the only subject who may transmit the gene to
the sixth generation. No protomutation carriers
were found in the fourth and fifth generations.
Therefore, it seemed highly probable that the DM
gene would be eliminated from this pedigree
within 1 generation.
Simmons et al.
(1998) demonstrated relatively stable
transmission of a (CTG)60 repeat allele through
3 generations of a large DM family; only 3
members, all offspring of male carriers, had
expansions in the clinically significant
range.
Barcelo et al.
(1994) insisted that there must be a
maternal 'additive' factor involved in
congenital DM. Their findings suggested that
while a high number of repeats seem to be a
necessary condition for congenital DM, this
alone is not sufficient to explain its exclusive
maternal inheritance. This was most clearly
reflected in the fact that in their study group,
approximately one-quarter of DM cases inherited
from affected fathers had repeat numbers equal
to or greater than those found in the congenital
DM cases with the lowest number of repeats
(approximately 700 repeats).
Novelli et al.
(1995) provided additional evidence that
size of repeat was insufficient to explain the
severity. Two affected mothers with similar
numbers of repeats gave birth to offspring with
discordant phenotypes. Childhood and congenital
myotonic dystrophy affected the son and the
daughter of one sister, with CTG triplet repeats
in lymphocytes of 700 and 1,100, respectively.
In contrast, the affected son of the other
sister had onset mild myotonic dystrophy at age
14 years, despite having 1,400 CTG triplets
detected in lymphocytes.
Hamshere et al.
(1999) found that in patients with CTG
expansions of greater than 1.2 kb, there was no
significant correlation between the age of onset
of symptoms and the size of their repeat.
Regression analysis predicted that the absolute
size of the CTG repeat may not be a good
indicator of the expected age of onset of
symptoms when the size of the repeat is 0.4 kb
or greater.
-
TRANSCRIPT AND PROTEIN
The CTG repeat is transcribed and is located
in the 3-prime untranslated region of an mRNA
that is expressed in tissues affected by
myotonic dystrophy. The polypeptide encoded by
this mRNA is a member of the protein kinase
family. Since the triplet repeat sequence is
within a gene that has a sequence similar to
protein kinases, Fu et
al. (1992) suggested that the gene be
referred to as myotonin-protein kinase.
Jansen et al. (1992)
demonstrated that the brain and heart
transcripts of the DM-kinase gene are subject to
alternative RNA splicing in both human and
mouse. The unstable (CTG)5-30 motif is found
uniquely in humans, although the flanking
nucleotides are also present in mouse. In both
species another active gene, called DMR-N9, was
found in close proximity to the DM-kinase gene.
DMR-N9 transcripts, mainly expressed in brain
and testis, possess a single large open reading
frame. The function of the protein product is
unknown. Clinical manifestations of myotonic
dystrophy may be caused by the expanded
CTG-repeat compromising the alternative
expression of DM-kinase or DMR-N9 proteins.
The involvement of a protein kinase in
myotonic dystrophy is consistent with the
pivotal role of such enzymes in a wide range of
biochemical and cellular pathways, and was
indeed predicted by Roses
and Appel (1974). Shaw
et al. (1993) demonstrated that the DMK gene
contains 15 exons distributed over about 13 kb
of genomic DNA. It encodes a protein of 624
amino acids with an N-terminal domain highly
homologous to cAMP-dependent serine-threonine
protein kinases, an intermediate domain with a
high alpha-helical content and weak similarity
to various filamentous proteins, and a
hydrophobic C-terminal segment. They also
isolated a second gene, located very close to
DMK and homologous to the mouse gene DMR-N9
(Jansen et al.,
1992). Strong expression of the latter gene
in brain suggested that it may play a role in
mental symptoms in severe cases of myotonic
dystrophy.
Mahadevan et al.
(1993) presented the genomic sequences of
the human and murine DM kinase gene. They
predicted a translation initiation codon and
determined the organization of the gene. Several
polymorphisms were identified within the human
gene, and PCR assays to detect two of these were
described.
Fu et al. (1993)
determined the genomic sequence of the gene that
they referred to as myotonin-protein kinase
(Mt-PK). In a length of 11,612 bp, the Mt-PK
gene contained a minimum of 14 exons. Several
forms of alternatively spliced mRNA were
demonstrated. By quantitative RT-PCR and by
radioimmunoassay using antisera they developed
against both synthetic peptides and purified
Mt-PK protein expressed in E. coli, Fu
et al. (1993) demonstrated that decreased
levels of the mRNA and protein expression are
associated with the adult form of myotonic
dystrophy. From this they suggested that the
autosomal dominant nature of the disease is due
to an Mt-PK dosage deficiency and that means of
elevating Mt-PK level or activity should be
explored for therapeutic intervention in adult
patients.
To determine the effect of the CTG repeat on
DM expression, Carango et
al. (1993) separated the chromosome 19
homologs from a 36-year-old woman with DM into
different cell lines by somatic cell
hybridization. RT-PCR amplification of coding
sequences from the DM gene showed both reduced
levels of primary DM transcripts and impaired
processing of these transcripts in the mutant
cell line. These findings suggested that the
presence of a large number of repeats in the
3-prime untranslated region of the DM gene
reduces both the synthesis and the processing of
DM mRNA, resulting in undetectable levels of
processed DM mRNA from the mutant allele.
Because nuclear histones are known to mediate
general transcriptional repression along
chromosomes, Wang et al.
(1994) used electron microscopy to examine
in vitro the nucleosome assembly of DNA
containing repeating CTG triplets. The
efficiency of nucleosome formation increased
with expanded triplet blocks, suggesting that
such blocks may repress transcription through
the creation of hyperstable nucleosomes. These
may alter the local chromatin structure, inhibit
the passage of transcription complexes, or
prevent the opening of the DNA before
replication. They may also result in DNA
polymerase slippage, pausing, or idling, leading
to expansion of the triplet block (Wang
et al., 1994). Wang
and Griffith (1995) performed competitive
nucleosome reconstitution to measure the
energetics of nucleosome formation over CTG
repeat blocks of n = 75 and n = 130. They showed
that these DNA fragments are 6 and 9 times
stronger in nucleosome formation, respectively,
than the 5S RNA gene of Xenopus borealis, one of
the strongest known natural nucleosome
positioning elements. These observations give
further support to the previously stated
hypothesis that expanded CTG blocks may alter
local chromatin structure.
Wong et al.
(1995) demonstrated that the expanded CTG
allele, which often presents as a diffused band
on Southern blot analysis, suggesting somatic
mutation, shows size heterogeneity that
correlates well with the age of the patients. In
their study, older patients showed larger size
variation. This correlation was independent of
the sex of either the patient or the
transmitting parent. Similar size heterogeneity
was not observed in congenital cases, regardless
of the size of expansion. It can be speculated
that continuous expansion of the CTG repeats is
related to the pathogenesis of the disease,
particularly the progression of the disease with
age.
The dominant inheritance of myotonic
dystrophy is difficult to rationalize with the
fact that the expansion mutation lies outside
the protein-encoding elements of the gene and
should not be translated into protein. Wang
et al. (1995) used muscle biopsies from
classic adult-onset myotonic dystrophy patients
to study the accumulation of transcripts from
both the normal and the expanded DM kinase genes
and compared the results to normal and myopathic
controls. They found relatively small decreases
of DM kinase RNA in the total RNA pool from
muscle; however, these reductions were not
disease-specific. Analysis of poly(A)+ RNA
showed dramatic decreases in both the mutant and
the normal DM kinase RNAs, and these changes
were disease-specific. Wang
et al. (1995) considered these findings
consistent with a novel molecular pathogenetic
mechanism for myotonic dystrophy in which both
the normal and expanded DM kinase genes are
transcribed in patient's muscle, but the
abnormal expansion-containing RNA has a
dominant-negative effect on RNA metabolism by
preventing the accumulation of poly(A)+ RNA. The
ability of the expansion mutation to alter
accumulation of poly(A)+ RNA in trans suggests
that myotonic dystrophy may be the first example
of a dominant-negative mutation manifested at
the RNA level.
-
PATHOGENESIS
- The mechanism by which the expanded
trinucleotide repeat in the 3-prime untranslated
region of the DMPK gene leads to the clinical
features is unclear. The DM region of chromosome
19 is gene rich, and it is possible that the
repeat expansion may lead to dysfunction of a
number of transcription units in the vicinity,
perhaps as a consequence of chromatin
disruption. Boucher et
al. (1995) searched for genes associated
with a CpG island at the 3-prime end of DMPK.
Sequencing of the region showed that the island
extends over 3.5 kb and is interrupted by the
(CTG)n repeat. Comparison of genomic sequences
downstream (centromeric) of the repeat in human
and mouse identified regions of significant
homology. This led to the identification of the
gene which Boucher et al.
(1995) called 'DM locus-associated
homeodomain protein' (DMAHP; 600963).
They found that this protein is expressed in a
number of human tissues, including skeletal
muscle, heart, and brain.
Harris et al.
(1996) reviewed the molecular genetics of
DM. They noted that published results on the
effect of the trinucleotide repeat in the
3-prime end of DMPK on the gene's transcription
have been contradictory. There were reports that
DMPK expression is increased at the
transcriptional level and reports that
transcription is decreased. They noted also that
the complexity of clinical manifestations in
myotonic dystrophy and the results of animal
studies suggest that other genes may be involved
in this disease. Harris
et al. (1996) reviewed results of studies on
mice in which DMPK had been homozygously deleted
(Jansen et al.,
1996), and studies in which a DMPK transgene
had been introduced to produce overexpression
(Reddy et al.,
1996). Harris et al.
(1996) concluded that the animal studies
ruled out haploinsufficiency of DMPK or
overexpression of DMPK as the only contributing
factor in DM. Harris et
al. (1996) postulated that other genes may
be involved. They proposed that the gene
encoding DM locus-associated homeodomain protein
(DMAHP), which lies immediately downstream of
the repeat, may play a role in DM.
Roberts et al.
(1997) used material from a DM homozygote
who had expansion of CTG repeats on both alleles
to study pathogenetic mechanisms in myotonic
dystrophy.
Otten and Tapscott
(1995) demonstrated that a
nuclease-hypersensitive site is positioned
adjacent to the CTG repeat at the wildtype DM
locus and that large expansions of the repeat
eliminated the hypersensitive site, converting
the region surrounding the repeats to a more
condensed chromatin structure. As
nuclease-hypersensitive sites often coincide
with gene regulatory regions, the decreased
accessibility of transcription factors to this
region in the expanded allele might affect local
gene expression. Therefore Klesert
et al. (1997) sought to determine whether
this hypersensitive site contained regulatory
elements that would enhance transcription in
fibroblasts or skeletal muscle cells, 2 cell
types in which the site was known to be present.
They found that the hypersensitive site contains
an enhancer element that regulates transcription
of the adjacent DMAHP homeo box gene. Analysis
of DMAHP expression in the cells of DM patients
with loss of the hypersensitive site revealed a
2- to 4-fold reduction in steady-state DMAHP
transcript levels relative to wildtype controls.
Thus the results demonstrated that CTG-repeat
expansions can suppress local gene expression
and implicate DMAHP in DM pathogenesis. Along
the same line, Thornton
et al. (1997) showed that DMAHP expression
in myoblasts, muscle, and myocardium was reduced
by the DM mutation in cis, and the magnitude of
this effect depended on the ex |
