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The Other Human Genome
Alan L. Shanske, MD;
Sara Shanske, PhD;
Salvatore DiMauro, MD
Arch Pediatr Adolesc Med. 2001;155:1210-1216.
ABSTRACT
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In the past 13 years, a new chapter of human genetics, "mitochondrial
genetics", has opened up and is becoming increasingly important in differential
diagnosis. Although the clinical manifestations of disorders related to mitochondrial
DNA (mtDNA) are extremely variable, recent advances in genetic testing aid
in the identification of patients. Muscle morphology can give important clues
for diagnosis, but histological features alone cannot define a specific disorder.
Biochemical analysis may reveal a single enzyme defect, or when multiple activities
are affected, suggest an mtDNA mutation. However, definitive diagnosis often
requires DNA analysis and documentation of a specific mtDNA abnormality. Disorders
associated with mtDNA mutations are associated with a wide variety of syndromes,
and owing to the properties and characteristics of mtDNA, these are often
transmitted by maternal inheritance. Although therapy for mitochondrial diseases
is limited, identification of the molecular defect is important for genetic
counseling.
INTRODUCTION
In addition to the nuclear genome, human cells also carry another, much
smaller set of genetic information—mitochondrial DNA (mtDNA). Because
of their ancestral origins as free-living bacterialike organisms, mitochondria
have their own DNA. This small, circular, double-stranded 16.5-kilobase (kb)
molecule is miniscule compared with the 3 million kilobases of nuclear DNA.
During the past 30 years, human mtDNA has been extensively investigated, and
as a result, it is one of the best-characterized portions of the human genome.
Its complete sequence has been determined, and its genetic content and mode
of expression have been clarified. Somewhat counterintuitively, this small
mtDNA has proven to be a seemingly inexhaustible site for deleterious mutations
that have been associated with a wide variety of syndromes.
In few fields of medicine has recent progress been as fast and exciting
as in the area of mtDNA defects. In the past 13 years, a new chapter of human
genetics, "mitochondrial genetics," has opened up and is becoming increasingly
important in differential diagnosis and genetic counseling. Although the clinical
manifestations of mtDNA-related disorders are extremely variable, recent advances
in genetic testing aid in the identification of patients. What makes these
diseases uniquely interesting from a genetic point of view is that mtDNA has
several distinctive features and is transmitted maternally.
In this article, we will summarize the features of mtDNA and its transmission
that are essential for understanding mtDNA-related disorders. We will then
briefly review the morphological and biochemical testing that can contribute
to the diagnosis of mitochondrial disorders, and go on to discuss the types
of mtDNA mutations described to date.
MITOCHONDRIAL GENETICS
Mitochondria are intracellular organelles that perform several vital
metabolic functions, the most important being generation of adenosine triphosphate
(ATP) through oxidative phosphorylation. Mitochondria are distinct from other
mammalian cellular organelles in that they contain their own genetic material,
mtDNA and are capable of synthesizing a small but vital set of proteins. This
dual genetic control makes mitochondrial diseases uniquely interesting from
a genetic point of view, as they can be due to mutations in either nuclear
DNA or mtDNA. Although mtDNA was discovered more than 30 years ago, its importance
in human pathology has become apparent only during the last 13 years, when
pathogenic mutations of mtDNA have been described in an increasing number.
Human mtDNA is a small, circular, double-stranded molecule 16.5 kb in
length (Figure 1). It contains 37
genes, which specify 2 ribosomal RNAs (rRNAs), 22 transfer RNAs (tRNAs), and
13 polypeptides. All 13 polypeptides encoded by mtDNA are components of the
respiratory chain or oxidative phosphorylation system and include 7 subunits
of complex I (nicotinamide adenine dinucleotide [NADH]–coenzyme Q [NADH-CoQ]
oxidoreductase), 1 subunit of complex III (CoQ–cytochrome c oxidoreductase), 3 subunits of complex IV (cytochrome c oxidase), and 2 subunits of complex V (ATP synthase). These 4 complexes
also contain approximately 75 subunits encoded by nuclear DNA that are imported
from the cytoplasm into the mitochondria.
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Map of the human mitochondrial genome. The structural genes for the
mitochondrial DNA–encoded subunits of nicotinamide adenine dinucleotide
[NADH]–coenzyme Q oxidoreductase (ND), cytochrome c oxidase
(COX), cytochrome b (Cyt b), and adenosine triphosphate
synthase (A8 and A6), in addition to the 12S and 16S ribosomal RNAs (rRNA)
and the amino acids specified by the 22 transfer RNAs are shown.
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There are several distinctive features of mtDNA that are relevant to
the understanding of mtDNA-related diseases.
Maternal Inheritance
At fertilization, all mitochondria are contributed by the oocyte; thus,
mtDNA is inherited only from the mother. Therefore, most mtDNA point mutations
are maternally inherited: a woman carrying an mtDNA point mutation will transmit
it to all of her children, males as well as females, but only the daughters
will transmit it to their progeny.
Heteroplasmy and Threshold Effect
In contrast to nuclear genes, each consisting of 1 maternal and 1 paternal
allele, there are hundreds or thousands of copies of mtDNA in every cell.
Thus, when there is a deleterious mutation, both normal and mutated mtDNAs
may coexist within a patient's tissues, a condition known as heteroplasmy. The situation in healthy individuals, in whom all mtDNAs
are identical, is called homoplasmy. Nondeleterious
mutations of mtDNA (neutral polymorphisms) are homoplasmic, whereas pathogenic
mutations are usually, but not always, heteroplasmic. A critical number of
mutated mtDNAs must be present before tissue dysfunction and clinical signs
become apparent (the so-called threshold effect). Tissues with high requirements
for oxidative energy metabolism, such as muscle, heart, eye, and brain, have
relatively low thresholds and are particularly vulnerable to mtDNA mutations.
Relatively low levels of mutated mtDNAs can affect the respiratory capacity
of these tissues, and high levels can be devastating. It is therefore not
surprising that most mtDNA disorders are encephalomyopathies, affecting primarily
brain and muscle.
Mitotic Segregation
At cell division, the proportion of mutant mtDNAs in daughter cells
can shift—a phenomenon termed mitotic segregation. If and when the pathogenic threshold for a particular tissue is exceeded,
the phenotype can change. Thus, in a patient who is heteroplasmic for a pathogenic
mutation, the clinical phenotype can change during the course of time. The
features of mtDNA are summarized in Table
1.
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Table 1. Features of Mitochondrial DNA*
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CLUES FOR DIAGNOSIS
Morphological
A modification of the Gomori trichrome histochemical stain allows for
the detection of abnormal deposits of mitochondria, which appear as reddish
blotches. These so-called ragged-red fibers (RRF) have become the signature
of mitochondrial myopathies. However, while the presence of RRF in muscle
biopsy specimens is a strong indication of a mitochondrial disorder, it is
important to keep in mind that RRF are not a prerequisite for the diagnosis
of mitochondrial disease.
Biochemical
Mutations in mtDNA often result in variable biochemical abnormalities,
but in some patients with documented mtDNA mutations, results of biochemical
studies are normal. Since the 13 proteins encoded by mtDNA are components
of 4 respiratory chain complexes, and only a portion of the mitochondrial
genome is mutated (heteroplasmy), the biochemical consequences of mtDNA mutations
in tRNA genes (see the "Genetic" subsection) are
usually partial deficiencies in multiple respiratory chain enzyme complexes.
The observation of combined defects of several complexes (except for complex
II, which is entirely encoded by nuclear DNA) should immediately suggest the
possibility of an mtDNA defect. In contrast, mutations in protein-coding genes
often result in a single specific enzyme defect. So respiratory chain enzyme
analysis can give clues as to whether and where in mtDNA to look for mutations,
but the definitive diagnosis of diseases due to mtDNA mutations relies on
DNA analysis.
Genetic
Since the initial descriptions of mtDNA deletions and point mutations
in 1988,1, 2 there has been a virtual
explosion of information linking mtDNA mutations to human diseases. Although
this situation may seem somewhat paradoxical considering that only 13 subunits
of respiratory chain complexes are encoded by mtDNA, while the approximate
75 remaining subunits are encoded by nuclear genes, this is probably explained
by the small size of mtDNA and the relative ease with which it can be studied.
Several different types of defects affecting mtDNA have been described (Table 2).
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Table 2. Mitochondrial DNA Defects and Associated Syndromes*
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mtDNA Point Mutations
The first point mutation in mtDNA was described in 1988,2
and this was associated with Leber's hereditary optic neuropathy. Since then,
more than 100 pathogenic mtDNA mutations have been documented,3, 4
and new ones are still being described. Point mutations are characterized
by single base changes, and these base substitutions can affect either a gene
involved in protein synthesis (a tRNA or rRNA gene), or a protein-coding gene (one of the 13 genes encoding
subunits of specific complexes of the respiratory chain).
Mutations Affecting Mitochondrial Protein Synthesis
Most point mutations described to date have been in tRNA genes. Since tRNAs are needed for translation
of the mtDNA-encoded proteins, all of the 13 mtDNA-encoded proteins can be
affected, thus explaining how these mutations affect multiple enzyme activities.
Numerous clinical observations have suggested that these mutations are usually
associated with multisystem disorders, lactic acidosis, and massive mitochondrial
proliferation in muscle, resulting in RRF.
The clinical phenotypes associated with pathogenic mtDNA point mutations
in tRNA genes vary widely and include devastating
encephalomyopathy, myopathy, optic neuropathy, progressive external ophthalmoplegia
(PEO), cardiomyopathy, diabetes and deafness, and isolated neurosensory hearing
loss.3, 4 Age at onset can be anywhere
between infancy and the fifth decade of life (or even later), but many patients
with mtDNA point mutations exhibit some symptoms in early childhood. Some
of these mutations have been reported in only one or a few families, while
others seem to be more common. The clinical features associated with 2 of
the more common mtDNA point mutations in tRNA genes,
MELAS (mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes),
and MERRF (myoclonus epilepsy and RRF) are presented in Table 3.
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Table 3. Clinical Features of Mitochondrial Encephalomyopathies*
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It has become apparent during the past several years that the A-to-G
transition at nucleotide position 3243 is the most frequently encountered
mtDNA point mutation, and that it can cause a spectrum of clinical presentations.
This was the third pathogenic mtDNA mutation to be reported5
and was originally described in patients with the MELAS syndrome.6 It was subsequently observed that maternal relatives
carrying this mutation could be oligosymptomatic and have diabetes, short
stature, migraine headaches, hearing loss, or other features either alone
or in various combinations.7 In addition, this
same mutation has been described in some patients with maternally inherited
PEO8 as well as diabetes and deafness.9 Age at onset is variable; in one study of 23 patients,
onset occurred between the ages of 1 and 53 years.7
Infantile occurrence, while infrequent, has also been reported.10
Pathogenic mutations in rRNA genes are rare.
The most common one is in the 12S rRNA gene (A1555G) and has been reported in families with aminoglycoside-induced
deafness or nonsyndromic hearing loss.11 Point
mutations in tRNA and rRNA
genes are transmitted maternally.
Mutations in Protein-Coding Genes
The most common mutations in protein-coding genes are associated with
2 disorders: Leber's hereditary optic neuropathy and NARP/MILS (neuropathy,
ataxia, and retinitis pigmentosa/maternally inherited Leigh syndrome).
The first point mutation reported in mtDNA was a G-to-A transition at
nucloetide position 11778 in patients with Leber's hereditary optic neuropathy,
a disorder characterized by acute or subacute onset of bilateral vision loss
in a young adult.2 The Leber hereditary optic
neuropathy is associated with 3 primary mutations in genes encoding subunits
of complex I of the respiratory chain: G3460A, G11778A, and T14484C.12 Mutations are usually homoplasmic, and muscle biopsies
do not show RRF.
A T-to-G mutation at nt8993 in the mtDNA gene
encoding adenosine triphosphatase (ATPase) 6 was initially described in patients
with a maternally inherited multisystem disorder characterized by NARP.13 Subsequently, the case of a family was reported in
which an adult male had the NARP syndrome and 3 children had MILS.14 This association has since been confirmed, and it
is now established that, for this particular mutation, there is a good correlation
between the percentage of mutant genomes (ie, degree of heteroplasmy) and
the severity of the clinical phenotype (ie, patients with low levels of mutation
are unaffected or have only mild symptoms, those with intermediate levels
have NARP, and those with very high levels [>95%] of mutation are associated
with MILS).15 Age at onset for MILS is infancy,
and it is characterized by developmental delay with psychomotor regression,
signs of brainstem dysfunction such as abnormal respiration and nystagmus,
and lactic acidosis; and, in most cases, the course is rapidly progressive.
The clinical features associated with these syndromes are presented in Table 3. A few additional point mutations
in the ATPase 6 gene have now been reported in association
with Leigh-like phenotypes, although clinical manifestations are milder than
those in patients with the T8993G mutation.16, 17
The mutations in the ATPase 6 gene are maternally
inherited and are not associated with RRF in muscle.
Recently, many mutations have been reported in the mtDNA cytochrome b gene18
and in genes encoding subunits of cytochrome c oxidase19, 20 and NADH-dehydrogenase.21
Interestingly, some of these patients had only exercise intolerance.18 While exercise intolerance is a common symptom in
patients with mitochondrial encephalomyopathies, it is often overshadowed
by other symptoms and signs. Only recently have we come to appreciate the
fact that exercise intolerance and myalgia, with or without myoglobinuria,
can be the sole presentation in patients with mtDNA mutations. While patients
with mutations in tRNA genes usually show maternal
inheritance, almost all patients with mutations in protein-coding genes have
been sporadic, with no evidence for maternal transmission. Additionally, in
most cases, these mutations were present only in muscle and were not detectable
in blood or fibroblasts. It is believed that these are somatic mutations,
ie, spontaneous events that occurred during embryogenesis in muscle after
germ layer differentiation and do not affect germ line cells.
Since family history does not provide any useful clues in these cases,
one must rely on laboratory testing (in which the presence of lactic acidosis
is a useful clue) or muscle biopsy findings. Morphological analysis often
shows the presence of RRF, and biochemical analysis shows decreased activity
for a specific complex of the respiratory chain: complex III in cases of cytochrome b mutations, complex IV or cytochrome c oxidase in patients with mutations in genes encoding cytochrome c oxidase subunits, or complex I in patients with mutations
in genes encoding subunits of NADH-dehydrogenase.
It is important to emphasize that most mitochondrial disorders are a
result of mutations in nuclear-encoded genes. For example, cytochrome c oxidase deficiency presenting as Leigh syndrome in infancy
is known to be an autosomal recessive disorder. These disorders are not reviewed
here. Our purpose is to point out that many mutations in mtDNA structural
genes have been documented, and to describe the clinical presentation of these
patients.
Diagnosis
Point mutations in mtDNA can be readily screened for, usually one at
a time, using a combination of polymerase chain reaction and restriction fragment
length polymorphism analysis. These analyses can establish, with certainty,
whether or not a particular point mutation is present. Of practical importance
is the fact that many of these mutations are detectable in DNA isolated from
blood; thus, a simple blood test can often establish the diagnosis. In some
cases, however, this analysis needs to be performed in DNA isolated from muscle.
mtDNA REARRANGEMENTS
Large-scale deletions in mtDNA were first reported in 1988,1 and shortly thereafter, it was shown they are present
in almost all patients with the Kearns-Sayre syndrome and in approximately
50% of patients with sporadic PEO and RRF.22
Although dozens of different deletions have been described, each patient harbors
only a single type of deletion, and the number of deleted genomes varies in
different patients and in different tissues from the same patient (heteroplasmy).
Virtually all patients with deletions in mtDNA have been sporadic; mothers
of affected individuals and children of affected women are clinically normal,
and when tested, they do not show deletions on muscle biopsies. This suggests
that deletions arise de novo early in embryogenesis or in the ovum.
Deletions in mtDNA are detected by Southern blot analysis, which shows,
in addition to the normal 16.5-kb mtDNA, a population of smaller mtDNA. Deletions
in mtDNA are best demonstrated by testing DNA isolated from muscle since most
patients with PEO and some patients with Kearns-Sayre syndrome do not show
deletions in DNA isolated from blood. Deletions in mtDNA are also detected
in blood from infants with Pearson syndrome, which is characterized by refractory
sideroblastic anemia, vacuolization of marrow precursors, and exocrine pancreas
dysfunction. These patients usually die in infancy, but the few who survive
go on to develop symptoms and signs of Kearns-Sayre syndrome.23
The clinical features associated with mtDNA deletions are presented
in Table 3. In addition to single
mtDNA deletions, some patients harbor more complex rearrangements in mtDNA,
which may include duplicated species. A duplication in mtDNA has been associated
with maternally inherited diabetes mellitus,24
so some mtDNA rearrangements may be maternally transmitted.
DEFECTS OF INTERGENOMIC SIGNALING
It is known that mtDNA requires several factors encoded by nuclear DNA
for its replication, transcription, and translation, but the interactions
between the nuclear and mitochondrial genomes are still poorly understood.
Thus, it is not surprising that some defects of mtDNA result from mutations
in nuclear DNA. Several disorders have been associated with multiple mtDNA
deletions, and in these patients, Southern blot tests of DNA isolated from
muscle show multiple bands representing species of mtDNA molecules harboring
deletions of different sizes. The first family to be described with multiple
mtDNA deletions had PEO that was transmitted as an autosomal dominant trait,25 and many cases of additional families with autosomal
dominant PEO have now been reported.3 Two families
with autosomal recessive PEO and multiple mtDNA deletions also had severe
hypertrophic cardiomyopathy.26 A distinctive
autosomal recessive multisystem disorder, mitochondrial-neuro-gastrointestinal
encephalopathy, is often, but not always, associated with multiple mtDNA deletions.27 Because of the mendelian mode of inheritance, these
disorders have been classified as defects of intergenomic signaling, ie, mutations
in nuclear genes that either facilitate an intrinsic propensity of mtDNA to
undergo rearrangements or impair recognition and elimination of spontaneously
occurring rearrangements.
Another defect of intergenomic signaling is mtDNA depletion syndrome,
a disorder of infancy or childhood in which the amount of mtDNA is severely
reduced in muscle or liver.28 At the molecular
level, this disorder is diagnosed by demonstrating a reduced ratio of mitochondrial
to nuclear DNA on Southern blot tests, but a definitive diagnosis requires
clinical, morphological, and biochemical correlations.29(pp97-108)
THERAPY
Treatment of patients with mitochondrial diseases is woefully inadequate
and is often limited to anecdotal cases or to trials that insufficiently allowed
for definite conclusions.29(pp173-198),30 One therapeutic approach has been aimed at the removal
of noxious metabolites, in particular lactic acid. Dichloroacetate, an experimental
agent, lowers serum lactate levels by its direct action on the pyruvate dehydrogenase
complex, and preliminary data are encouraging.31
Another approach is supplementation of respiratory chain components. The frequent
reports of subjective or objective beneficial results and the virtual lack
of deleterious adverse effects have encouraged the use of CoQ10,
often in conjunction with L-carnitine. The administration of vitamins, especially
thiamin and riboflavin (cofactors of mitochondrial enzymes), is also a common
practice for patients with mitochondrial diseases.
CONCLUSIONS
Patients suspected of having a mitochondrial encephalomyopathy need
to be evaluated at several levels, and relevant studies are presented in Table 4. The diagnostic process starts
with a careful clinical assessment and family history. For example, the involvement
of extraocular muscles or the presence of maternal inheritance suggests the
possibility of an mtDNA mutation. Laboratory tests (such as elevated blood
lactate values) and neuroradiological findings offer clues as to mitochondrial
etiology. While molecular studies in DNA isolated from blood can sometimes
provide a diagnosis, a muscle biopsy is often required. The importance of
muscle histology and histochemistry cannot be overestimated. While the presence
of RRF confirms mitochondrial dysfunction, the absence of RRF does not rule
out mitochondrial disease. Biochemical studies in muscle may provide a definitive
diagnosis (eg, a deficiency of a specific enzyme) or provide clues pointing
to the possibility of an mtDNA defect (eg, partial deficiencies of multiple
enzyme activities). Molecular genetic studies of DNA isolated from muscle
are often necessary for the detection of point mutations as well as mtDNA
deletions.
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Table 4. Evaluation of Patients With Suspected Mitochondrial Encephalomyopathy
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In summary, histological features can be important for diagnosis and
classification, but morphological features are neither specific nor sensitive
enough to define mitochondrial disorders. Single enzyme defects can be determined
by biochemical analysis in the affected tissue(s), and these are usually the
result of either nuclear DNA defects or mutations in mtDNA protein-coding
genes. Mutations in mtDNA can be diagnosed by DNA analysis, often in DNA isolated
from blood. Because of the properties and characteristics of mtDNA, these
disorders have variable clinical presentations and are usually transmitted
by maternal inheritance. Therapy for mitochondrial diseases is limited; however,
the rationale for the use of certain compounds, such as carnitine, CoQ10, and many vitamins is sufficient justification of their use in individual
patients.
AUTHOR INFORMATION
Accepted for publication August 9, 2001.
Some of the work described here was supported by grants PO1HD32062 and
NS11766 from the National Institutes of Health (Bethesda, Md) and by a grant
from the Muscular Dystrophy Association (Tucson, Ariz).
From the Center for Congenital Disorders, Children's Hospital at Montefiore,
Albert Einstein College of Medicine, Bronx, NY (Dr A. L. Shanske), and the
Department of Neurology, Columbia College of Physicians and Surgeons, New
York, NY (Drs S. Shanske and DiMauro).
Corresponding author and reprints: Alan L. Shanske, MD, Center for
Congenital Disorders, Montefiore Medical Center, 111 E 210th St, Bronx, NY
10467 (e-mail: ashanske{at}montefiore.org).
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