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From the Cardiovascular Pathology and Molecular
Diagnostic*
and Research Transplantation
Laboratories
and the Departments of
Cardiology
and Cardiac
Surgery,||
Istituto di Ricovero e Cura a Carattere
Scientifico (IRCCS) Policlinico San Matteo, Pavia, Italy; Children's
Hospital of Philadelphia,§
University of
Pennsylvania, and Allegheny University Hospitals of Health
Sciences,¶ Philadelphia, Pennsylvania
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Mitochondrial tRNA gene mutations variably affect activity of the respiratory chain complexes. Activity of complex II is not affected as it is entirely encoded by nuclear DNA, whereas cytochrome C oxidase (Cox) activity (or complex IV), which is partially encoded by mtDNA genes and constitutes the electron transport chain along with complex I,12 is frequently reduced in patients with mtDNA tRNA mutations. Pathological tRNA mutations are characteristically heteroplasmic and absent from controls and affect highly conserved regions;12,13 tRNA mutations have been reported in patients with hypertrophic cardiomyopathy, particularly in those who develop late congestive heart failure14 or with not otherwise defined cardiomyopathies and congestive heart failure.5,6,9 Rarely, missense mutations in polypeptide-coding genes have been linked to multisystem syndromes.15 Ultrastructural mitochondrial changes and enzyme defects characterize affected tissue in mtDNA-related disorders.7,11,12,16 Similar ultrastructural mitochondrial changes and enzyme defects may be found in part of the cardiomyopathies.2,4,9,17,18
Although molecular mitochondrial abnormalities constitute an attractive basis of development of dilated cardiomyopathy (DCM), the prevalence and characteristics of mtDNA mutations have not been extensively studied. In the present study, we attempted to determine the prevalence of mitochondrial abnormalities associated with mtDNA mutations in a large cohort of patients with idiopathic DCM and to assess whether mtDNA mutations were unique, heteroplasmic, localized to conserved regions, and absent in healthy controls, thus fulfilling the requisites for being accepted as having a pathological role. The genetic analysis was performed to identify mutations in tRNA, ribosomal (r)RNA, and flanking regions of mtDNA. The selection of cases for molecular analyses was based on mitochondrial ultrastructural changes in the endomyocardial biopsies (EMBs) of the patients. The study also evaluated the activity of oxidative enzyme complex (Cox, succinate dehydrogenase, (SDH), and the reduced form of nicotinamide-adenine dinucleotide (NADH) dehydrogenase).
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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A 10-year series of 601 consecutive DCM patients was evaluated in the Department of Cardiology at the IRCCS Policlinico San Matteo, Pavia, Italy. All patients underwent clinical examination, biochemical investigations (creatine-phosphokinase (CPK) and lactic dehydrogenase (LDH)), electrocardiography, chest x-rays, two-dimensional and Doppler echocardiography, right and left heart catheterization, coronary angiography, and right ventricular EMB.
Biopsy specimens from all patients, in addition to routine histological
study, were evaluated ultrastructurally and immunohistochemically. Of
the 601 patients, 85 (ages 16 to 63 years; mean age, 43.5 ± 12.7;
67 males and 18 females) had a combination of the following peculiar
mitochondrial ultrastructural abnormalities: mitochondrial
proliferation and variable matrix density associated with giant
ring-shaped mitochondria, concentric, angulated, and tubular cristae,
crystalloid and osmiophilic inclusion bodies, and glycogen or lipid
inclusions. Cristolysis, swelling, and variable size of mitochondria
were considered as nonspecific changes. In the 67 male patients,
defects of dystrophin immunolabeling with specific anti-COOH-terminus,
NH-terminus, and rod domain antibodies (Novocastra, Newcastle, UK) were
not identified. The biopsy specimens from these 85 patients were
subjected to molecular analysis for mutations in mtDNA, tRNA, rRNA, and
flanking regions. Of the 516 DCM patients without the ultrastructural
changes considered for screening, 32 random cases (25 males; mean age,
41.3 ± 10.7 years) were selected as affected controls. Controls
for mtDNA analysis were enrolled from the blood donor pool (see below).
For comparative enzyme activity tests, normal myocardial tissue samples
were obtained as right ventricular biopsies from in-hospital donor
hearts before transplantation (EKG, echo, clinical, and biochemical
evaluation; n = 6; 5 males; mean age, 38 ± 11
years) when total ischemic time was 
60 minutes.
Endomyocardial Biopsy and Pathological Study
Five to seven right ventricular EMB samples were obtained for each patient and processed for light microscopy and ultrastructural study.19-22 Sections were examined with a Zeiss 902 electron microscope. One frozen sample was used for nucleic acid extraction and genetic analysis. In 17 DCM cases (5 with mtDNA mutations and 12 without mtDNA mutations) that underwent cardiac transplantation later on in the course of the disease, we evaluated the mitochondrial Cox, NADH dehydrogenase, and SDH activity in myocardial tissue.23-25 Pretransplant biopsies of six normal donor hearts were used as controls.
Mitochondrial DNA Study
Molecular analysis of mitochondrial DNA was performed both in the EMB samples as well as in peripheral blood of the 85 patients with ultrastructural mitochondrial abnormalities. Control blood samples were obtained from 111 healthy, age- and sex-matched blood donors (ages, 18 to 60 years; mean age, 39 ± 8 years; 83 males and 28 females). The control subjects were ensured to have normal electrocardiogram and biochemical parameters including CPK and LDH. Whenever a mtDNA mutation was identified, all available maternal relatives of the probands were also tested for the given mutation (n = 49 for the 85 patients).
For molecular analysis, total genomic DNA was extracted from EMBs and
from peripheral blood samples. Specific oligonucleotide primers were
synthesized. The selected regions were amplified by polymerase chain
reaction (PCR) and subjected to denaturing gradient gel electrophoresis
(DGGE) for tRNA and rRNA or to single-strand conformational
polymorphism (SSCP) for coding regions26
for mutation
screening. The abnormal conformers underwent direct DNA sequencing for
identification of mutation sites, followed by restriction enzyme
digestion to assess heteroplasmy of each given mutation and by repeated
densitometric analysis to quantify the amount of mutant in the heart
and peripheral blood DNA (Tables 1 and 2)
.
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Total genomic DNA was isolated from heart and blood samples with conventional methods.27 Oligonucleotide primers encompassing the 22 tRNA, 2 rRNA, and coding genes were designed,28 synthesized with a 392 DNA-RNA synthesizer (Applied Biosystems, ABI, Foster City, CA), and purified with oligonucleotide purification cartridges (Applied Biosystems). Primers with GC clamps were synthesized for DGGE.
PCR
Selected mtDNA regions were amplified by PCR from 0.1 µg of the total DNA in an automated thermal cycler (Perkin Elmer Cetus Gene Amp PCR system 9600). Amplifications were performed in 50 µl of reaction solution containing 100 ng of genomic DNA, 200 mmol/L each dNTP, 1 mmol/L each primer, 1.25 U of AmpliTaq Gold DNA polymerase (Perkin Elmer), and PCR buffer (10 mmol/L TrisHCl, pH 8.4, containing 50 mmol/L KCl, 1.5 mmol/L MgCl2, and 0.01% gelatin) after denaturation for 10 minutes at 94°C. PCR conditions are available on request. Amplified fragments were separated by electrophoresis on 2% agarose gel and stained with ethidium bromide.
DGGE and SSCP
Screening for mutations was performed with DGGE and/or SSCP analysis.29,30 Single-stranded DNA was visualized with standard silver nitrate staining. Cases with abnormal DGGE or SSCP conformers were selected for automated DNA sequencing.
Automated DNA Sequencing
The double-stranded DNA fragments were purified with Centri-sep columns (ABI Perkin Elmer) and used for cyclic sequencing with the Taq DyeDeoxy Terminator cycle sequencing kit in a 373A DNA sequencer (ABI Perkin Elmer) under conditions recommended by the manufacturer. Sequence comparison and analyses were performed with the Sequencher TM 3.0 software (Gene Codes Corp., Ann Arbor MI).
Heteroplasmy Assessment
Although heteroplasmy can be suspected on DGGE pattern, most
heteroplasmic mutations with a high amount of mutated DNA appeared to
be homoplasmic according to the sequencing pattern. Thus, to assess the
heteroplasmy of any given mutation, we used restriction enzyme
analysis; for mutations that gained or lost restriction enzyme sites,
the PCR fragments were digested with the enzyme and electrophoresed
through an 8% nondenaturing polyacrylamide gel. For mutations that did
not modify the restriction enzyme map, we synthesized a forward or
reverse mismatch primer that, in combination with any given mutation,
gained or lost a restriction enzyme site. Then, both digestion and
electrophoresis were performed as above. The relative amounts of the
mutant mitochondrial genomes were quantitated with a Bio-profile Bio-1D
blot analyzer (Vilber Lourmat Biotechnology Division, Marne La Vallee,
France). The mismatch sites for pathological mutations found in the
study are detailed in Tables 1 and 2
.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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. Of the 85 patients, 19 (22.35%) had
mtDNA mutations that were not found in normal and diseased controls
(Table 1)
. Cox enzyme activity (Table 3)
was severely affected, with significantly lower mean levels in the
myocardium of patients with mtDNA mutations compared both with that of
nonmutated DCM patients without mitochondrial abnormalities and with
that of normal controls (P = 0.0008). NADH
dehydrogenase activity was slightly reduced in DCM with mtDNA mutations
(P = 0.0388), whereas differences in SDH
activity in patients and controls did not reach significant values.
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We identified nine tRNA, five rRNA, and five missense mutations. In addition, polymorphic changes were seen both in controls (n = 111) and in DCM subjects with (n = 85) and without (n = 32) mitochondrial ultrastructural changes.
Transfer RNA Mutations
Of the 85 patients, 9 had heteroplasmic mutations in 6 of the 22
tRNA (Figures 2 and 3)
. Five mutations affected tRNA stems,
and four affected the loops. The tRNA mutations were present both in
blood and in heart mtDNA, but the amount of mutated DNA was higher in
heart than in blood and varied from case to case (Figures 2 and 3)
. All
nine patients had unique mutations. Two patients had familial
cardiomyopathy. The seven remaining patients had sporadic forms. Most
mutations occurred in bases that are highly or moderately conserved
through evolution (alignments are available on request).
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Heteroplasmic mutations in the 12 S rRNA and in the 16 S rRNA were
found in five unrelated patients with sporadic DCM (Figure 3)
.
Analogously to tRNA mutations, the amount of mutated DNA was higher in
heart than in blood. All five mutations were not seen in control
myocardial or blood samples.
Missense Mutations
Missense heteroplasmic mutations, with a higher amount of mutant DNA in heart than in blood, were identified in five cases. One (G3316A) was familial (sister and mother died of DCM). Two unrelated patients shared an identical mutation (A5510C) in the ND2 gene; these two patients also had similar clinical history, morphology, and outcome.
Polymorphic mtDNA Changes in DCM Patients and Controls
A series of known neutral polymorphisms, most of which were
homoplasmic, was identified in both patients and controls (mutations
and relative frequencies in cases and in controls are available on
request). Three tRNA neutral polymorphisms in three different patients
(T4336C, T10034C, and A10398G) were absent in controls and
heteroplasmic at repeated restriction enzyme digestions (Table 2)
. In
addition, three other patients carried the T4216C, Tyr-Lys homoplasmic
LHON mutation, which was also found in three controls. Three
homoplasmic mutations, T14766C Ile-Thr (16.4% of patients
versus 14.4% of controls), T14798C Phe-Leu (10.5% of
patients versus 12.6% of controls), and G15884A Ala-Thr
(1.1% of patients versus 0.9% of controls), were missense
and were found in patients but also in healthy controls. All other
mutations in polypeptide-coding genes were synonymous.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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All pathological mutations were heteroplasmic, had a higher proportion of mutant in the affected heart than in the corresponding blood, and were not detected in controls. Some of the mutations occurred at nucleotide positions highly conserved through evolution (ie, A5600T tRNAAla), whereas other mutations affected moderately (such as A4315G tRNAIle) or less conserved (such as T7581C tRNAAsp, or A15902G tRNAThr) positions. Previously described mtDNA mutations with similar evolutionary conservation (eg, T3271C) have been proven to be involved in the pathogenesis of mitochondrial encephalomyopathies.31 The nucleotide position of the mutation in any given tRNA may be related to the effects; in the tRNA stems, the mutations disrupt highly conserved base pairs, whereas in the tRNA loops, the mutations adversely affect the clover leaf structure of tRNAs. The functional relevance of rRNA mutations is less clear. As ribosomes are fundamental for translation mechanisms, rRNA mutations may cause major assembly defects or interfere with tRNA protection activity.32 Additional studies are needed to elucidate the possible pathogenic role of rRNA mutations.
We attributed a pathological significance only to heteroplasmic
mutations with a higher amount of mutated DNA in heart than in
peripheral blood (Table 1)
. In general, the threshold of mutated DNA in
the affected organ varies from one mutation to the other and is
influenced by the functional significance of a given base change.
Myocardial samples from the maternal relatives of our patients were not
available, and mutations could be evaluated only in their peripheral
blood DNA. Due to the heteroplasmic characteristics of the mutations,
the difference in mutant DNA in blood of patients and of unaffected
relatives does not necessarily reflect identical gradients in
myocardial tissue. Therefore, the evaluation of the amount of mutant
DNA in blood of relatives does not provide any information about the
likelihood of occurrence of cardiomyopathy. We are following up
unaffected mutated relatives. If the cardiomyopathy phenotype indeed is
related to the amount of mutated mtDNA in the affected organ as in
encephalomyopathies,13
clinical follow-up of mutated but
healthy relatives should allow early detection of disease. A recent
study done in 58 unrelated patients with DCM showed that mtDNA point
mutations are significantly more frequent in patients than in controls.
Of the 43 mutations identified, 4 were heteroplasmic and affected
evolutionarily conserved regions.33
None of these
mutations, as well as none of the mutations previously reported in
patients with cardiomyopathy, was identified in our series, supporting
the uniqueness of missense mutations found to date in
cardiomyopathies.
All pathological heteroplasmic mutations were absent from our normal and diseased control subjects. However, it would not be surprising if some of these mutations were subsequently considered as polymorphic changes. For instance, Lauber et al originally proposed that the A12308G transition in the tRNALeuCUN gene in four patients with mitochondrial encephalomyopathy was associated with the disease because it occurred at a site that had been highly conserved in various species during evolution and was not present in the general population.34 A subsequent study showed that this mutation, with a frequency of 16%, was also present in the general population.35 The same considerations applies to the LHON 4216 mutation, which seems to contribute to the disease only when interacting with other mutations;15,35 such a mutation has not been considered, by itself, to be pathological in our patients.
Although the heart was the only clinically affected organ in our patients, we cannot exclude the presence of subclinical skeletal myopathies, particularly in the patient with the A3260G mutation.5 Clinically overt peripheral myopathy did not occur in the other cases with family history of cardiomyopathy and congestive heart failure of the present series. Furthermore, none of our patients had diabetes mellitus or other disorders that may be associated with pathological mtDNA mutations. Compared with severe mitochondrial phenotypes affecting children (such as MELAS), our mutations were associated with a relatively milder phenotype. Most of our patients were young adults or adults, and most of them had a slowly evolving illness. It is not unlikely that in addition to the dose of mutant DNA in the affected myocardial tissue, the unique characteristics of the tissue itself could influence the phenotype. As such, post-mitotic or slowly dividing tissue cells that are highly dependent on mitochondrial oxidative function (such as myocardium) may be affected only when the proportion of the mutated DNA is considerably high. The resulting dysfunction in the overall mtDNA activity could impair oxidative phosphorylation processes and reduce the supply of the energy necessary for the contractile function of cardiac myocytes, thus leading to chronic heart failure. Although the mitochondrial cardiomyopathies may appear less severe than most encephalomyopathies, they often show inexorable progression of chronic heart failure and may be equally fatal.
mtDNA mutations fulfilling pathological criteria occurred in approximately one-fourth of our DCM patients with ultrastructural mitochondrial abnormalities. Furthermore, biochemical study showed a significant decrease in Cox activity and in NADH dehydrogenase activity in myocardial tissue obtained from patients who subsequently underwent heart transplantation. For the remaining three-fourths of cases with abnormal mitochondrial ultrastructure, either nuclear DNA mutations or signaling defects can be hypothesized, based on the mitochondrial and nuclear DNA interactions and on the nuclear DNA contribution to the synthesis of the respiratory chain enzymes.36,37
A limit of the present study is that we cannot exclude a priori that DCM patients with nonspecific mitochondrial changes carry mtDNA mutations. However, no pathological mutation was identified in the 32 DCM cases with nonspecific ultrastructural mitochondrial changes.
Furthermore, it cannot be stated that mtDNA mutations were the only DNA defects in these patients. In a recent report we have described the association of mtDNA mutations plus ß-myosin heavy chain gene mutations in patients with hypertrophic cardiomyopathies complicated by congestive heart failure evolution.38 In these hypertrophic cardiomyopathy patients we also found a severe reduction in Cox activity in the heart and a wide spectrum of mitochondrial ultrastructural abnormalities. Therefore, we cannot exclude that mtDNA mutations may act as cofactors to unidentified pathological nuclear gene mutations.
The present study provides evidence that pathological mtDNA mutations may occur in a small proportion of otherwise idiopathic DCM cases. These mutations carry the same characteristics that define pathogenicity in mitochondrial encephalomyopathies and are associated with ultrastructurally abnormal mitochondria and decreased Cox activity. The findings support the hypothesis that in a small subset of patients, mitochondrial DNA defects may constitute the basis for, or contribute to, the development of dilated cardiomyopathy and congestive heart failure.
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Footnotes |
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Supported by grants RF-IRCCS Policlinico San Matteo, Pavia 1992–1995.
Accepted for publication August 5, 1998.
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References |
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C). Clin Genet 1994, 45:109-110[Medline]
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