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Autosomal dominant chronic progressive external ophthalmoplegia A tale of two genomes.

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Autosomal Dominant
Chronic Progressive
External Ophthalmoplegia:
A Tale of Two Genomes
Large deletions in mitochondrial DNA (mtDNA) were
first reported in a group of patients with mitochondrial
myopathy [ 11. Subsequent studies established that they
were particularly associated with two disease phenotypes-chronic
progressive external ophthalmoplegia
(CPEO) and the multisystem disorder Kearns-Sayre
syndrome (KSS)-both
of which are usually sporadic
diseases [2, 31. T h e skeletal muscle in these patients
contains, in addition to wild-type mtDNA, a single
molecular species of deleted mtDNA, which can be
easily visualized by Southern blot analysis. The widespread tissue distribution of the same deleted molecule
in individual patients suggests that the mutation arises
as a clonal event in the female germline or early embryo. Why such deletions are apparently not transmitted by carrier females remains a mystery.
In addition to the more common sporadic cases, an
autosomal dominant form of CPEO (AD CPEO) has
been described in which multiple different mtDNA deletions accumulate in the skeletal muscle (and other
tissues) [4, 51. O n Southern blots these deletions appear as a smear, sometimes containing multiple discrete
bands, below the wild-type mtDNA, reflecting the
presence of a large number of different molecular species of deleted mtDNAs. Because of the autosomal
mode of inheritance, this form of the disease is thought
to result from a communication error between the nuclear and mitochondrial genomes. Recent attempts to
map the defective gene in families with A D CPEO
revealed a surprising amount of underlying molecular
heterogeneity. Linkage to chromosome 1Oq has been
established in a large Finnish family [ 5 ] and to 3p in
several Italian families 161. In a third group of Italian
families, linkage to either of these loci has been excluded [ 6 ] .Thus, at least three independent nuclei loci
can produce a similar clinical phenotype. In addition, autosomal recessive (AR) CPEO with multiple
m t D N A deletions was recently documented in two unrelated Arab families 171.
T h e skeletal muscle in patients with sporadic CPEO
is characterized by the presence of numerous raggedred fibers, most of which are negative for cytochrome
c oxidase, a marker of mitochondria1 respiratory chain
activity [8]. This biochemical defect results from the
focal accumulation of deleted mtDNA in affected muscle fiber segments. All large m t D N A deletions remove
at least one transfer RNA (tRNA) gene. When mutant
genomes predominate, mitochondrial translation is
impaired and the polypeptides that are encoded in
mtDNA, which are essential for respiratory chain function, are not produced.
While the skeletal muscle pathology in patients with
A D CPEO is substantially similar to that in patients
with single deletions, the molecular basis for the biochemical phenotype has not been characterized at the
cellular level. T h e paper by Moslemi and colleagues in
this issue [9] provides important new information in
a Swedish family with AD CPEO. The presence of
multiple different deletions in the skeletal muscle of
their patients could theoretically reflect one of two patterns at the cellular level. Affected muscle fibers could
contain several different species of deleted mtDNA, the
result of their continuous generation, or alternatively,
such fibers could contain single different deletions, reflecting the clonal expansion of relatively rare events.
Using a combination of in situ hybridization and single-fiber polymerase chain reaction (PCR) techniques,
Moslemi and colleagues convincingly demonstrated
that while different deletions are associated with different affected muscle fibers, each contains a clonal expansion of one molecular species of deleted mtDNA.
This pattern, the clonal expansion of a single species
of deleted mtDNA, is strikingly similar to that observed in the skeletal muscle from older individuals
[ 101 and in patients with sporadic inclusion body myositis (IBM) [ 1 11. Multiple deletions accumulate with
age in normal individuals 1121, but this usually only
results in a few scattered ragged-red fibers [lo]. An
exaggerated form of this process has, however, been
detected in a group of patients with so-called late-onset
(after the age of 65 years) mitochondrial myopathy,
in whom ragged-red fibers were about ten times more
numerous than in age-matched control subjects [ 101.
T h e molecular defect in IBM is unknown and the presence of multiple mtDNA deletions, while likely contributing to the skeletal muscle pathology in many patients, is thought to be a secondary phenomenon [ 1 1].
Structural changes in the nucleus in the skeletal muscle
Copyright 0 1996 by the American Neurological Association
of patients with sporadic IBM suggest the involvement
of a factor important in nuclear function. ‘Thus, it
seems very likely that there is a continuum involving
essentially the same molecular process in the context
of a variety of phenotypes, with normal aging at one
end of the spectrum and AD CPEO a t the other.
Although the molecular mechanism that produces
large mtDNA deletions remains unknown, it is likely
that they are generated as errors of mrDNA replication
[ 131. mtDNA contains many short repeated sequences
and the majority of deletions have such sequences at
or near the deletion breakpoints [ 131. Replication of
the two strands of the circular m t D N A molecule occurs
asymmetrically from two independent and widely separated origins [14]. As a result one strand of mtDNA
is left single stranded for an extended period during
replication, until such time as the other replication origin is exposed. This situation could permit inappropriate association of a repeated sequence on one strand
with a complementary sequence at a different location
on the other strand, ultimately resulting in the loss of
the DNA between the two repeated sequences.
This hypothesis is attractive because it implies that
any factor which increased the probability of these
events would generate deletions at a higher frequency.
This could be part of the replication apparatus itself,
part of the machinery that regulates productive
mtDNA replication, or any environmental factor that
impinges on mitochondrial function. In this view, the
genetic defects associated with AD CPEO increase
somewhat the low but finite probability of making a
replication error that produces a m t D N A deletion.
This would explain why individual affected fibers have
single deletions and why this is a progressive disease
with relatively late onset. Once produced in a postmitotic cell like skeletal muscle, the ultimate fate of the
deletion is expansion (due to some form of replicative
advantage), at the expense of wild-type mtDNAs. A
clinical phenotype results only when the proportion of
deleted mtDNAs exceeds the threshold for expression
of a pathogenic biochemical phenotype in a sufficient
number of muscle fibers.
T h e next major step forward in this field will clearly
involve finding the gene defects in AD and AR CPEO.
O n e good candidate, a mitochondrial single-stranded
DNA-binding protein thought to protect against inappropriate strand associations during replication, has
already been ruled out in families showing linkage,
because it maps to chromosome 7q 1151. T h e
identification of [he genes involved in these rare disorders will likely provide some fundamental insights into
694 Anrials of Neurology
Vol 40
No 5
the mechanisms that govern the 6aithful replication and
maintenance of mtDNA.
Eric A. Shoubridge, PbD
Moatred Neurological Institute mid Depnrtmeiit
of Hiininn Genetics
McGill Uiaiucrsity
Montred, Quebec, Canadn
November 1996
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autosomal, two, progressive, dominantly, tales, genome, ophthalmoplegia, external, chronic
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