(Circulation. 2001;103:1256.)
© 2001 American Heart Association, Inc.
Clinical Investigation and Reports |
Novel Gene Mutations in Patients With Left Ventricular Noncompaction or Barth Syndrome
From the Department of Pediatrics, Toyama Medical and Pharmaceutical University, Toyama (F.I., S.T., K.U., T.M.), and Department of Pediatrics, Shimane Medical University (N.H.), Japan; the Departments of Molecular and Human Genetics (K.R.B., J.A.T.), Pediatrics (Cardiology) (W.J.D., H.L., N.E.B., J.A.T.), and Cardiovascular Sciences (J.A.T.), Baylor College of Medicine, Texas Children’s Hospital, Houston, Tex; and the Children’s Hospital at St Joseph’s, Paterson, NJ (J.M.).
Correspondence to Jeffrey A. Towbin, MD, Department of Pediatrics (Cardiology), Baylor College of Medicine, One Baylor Plaza, Room 333E, Houston, TX 77030. E-mail jtowbin{at}bcm.tmc.edu
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Abstract |
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Background—Mutations in the gene G4.5 result in a wide spectrum of severe infantile cardiomyopathic phenotypes, including isolated left ventricular noncompaction (LVNC), as well as Barth syndrome (BTHS) with dilated cardiomyopathy (DCM). The purpose of this study was to investigate patients with LVNC or BTHS for mutations in G4.5 or other novel genes.
Methods and Results—DNA
was isolated from 2 families and 3 individuals with isolated LVNC or
LVNC with congenital heart disease (CHD), as well as 4 families with
BTHS associated with LVNC or DCM, and screened for mutations by
single-strand DNA conformation polymorphism analysis and DNA
sequencing. In 1 family with LVNC and CHD, a C
T mutation was
identified at nucleotide 362 of
-dystrobrevin, changing a
proline to leucine (P121L). Mutations in
G4.5 were identified in 2
families with isolated LVNC: a missense mutation in exon 4 (C118R) in 1
and a splice donor mutation (IVS10+2TA) in intron 10 in the other.
In a family with cardiomyopathies ranging from BTHS or fatal infantile
cardiomyopathy to asymptomatic DCM, a splice acceptor mutation in exon
2 of G4.5 (398-2 AG) was
identified, and a 1-bp deletion in exon 2 of G4.5, resulting in a stop
codon after amino acid 41, was identified in a sporadic case of
BTHS.
Conclusions—These data
demonstrate genetic heterogeneity in LVNC, with mutation of a novel
gene, -dystrobrevin,
identified in LVNC associated with CHD. In addition, these results
confirm that mutations in G4.5
result in a wide phenotypic spectrum of
cardiomyopathies.
Key Words: cardiomyopathy • genetics • heart defects, congenital
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Introduction |
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Left ventricular noncompaction (LVNC) is reportedly rare and has been thought to be due to an arrest of myocardial morphogenesis.1 This disorder is characterized by a hypertrophic LV with deep trabeculations and with poor systolic function, with or without associated LV dilation.2 3 In some cases, the right ventricle is also affected. No congenital heart defects (CHDs) are seen in these patients. Similar myocardial patterns are occasionally reported postnatally in association with congenital heart anomalies2 such as ventricular septal defects (VSDs), pulmonic stenosis, and atrial septal defects. This has been called nonisolated LVNC or LVNC associated with CHD. Although the genetic cause of LVNC with CHD is unknown, recent studies using genetic linkage and mutation analysis identified mutations in the gene G4.5 in patients with isolated LVNC.4 G4.5 was initially associated with Barth syndrome (BTHS),5 a disease first described by Neustein et al6 and Barth et al,7 and encodes a novel protein family called the tafazzins. BTHS is a clinical association that includes skeletal myopathy and either endocardial fibroelastosis or dilated cardiomyopathy (DCM), neutropenia, abnormal mitochondria, growth retardation, abnormal cholesterol metabolism, lactic acidosis, elevated urinary 3-methylglutaconic acid and 2-ethylhydracrylic acid, and X-linked recessive inheritance. Mutations in G4.5 result in not only BTHS but also other X-linked infantile cardiomyopathies, including LVNC,4 X-linked infantile cardiomyopathy,8 9 and X-linked endocardial fibroelastosis.8
Myocardial disorders affecting systolic function but without
deep trabeculations have also been seen in animal models or human
patients with mutations disrupting the dystrophin
gene10 11 or its
interaction with other proteins, such as the dystrophin-associated
glycoprotein complex
(DAPC)12 or the sarcomere
(actin, muscle LIM
protein).13 14 In
this report, we identify a mutation of the gene for
-dystrobrevin, a cytoskeletal protein in the DAPC, in a
family with LVNC with CHD. In addition, we describe novel
G4.5 mutations in individuals
with isolated LVNC, as well as in patients with BTHS and other
forms of DCM, including a family with widely variant phenotypic
presentations, thus extending the phenotypic spectrum of patients with
mutations in
G4.5.
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Methods |
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Clinical Diagnostic Criteria
LVNC was diagnosed by echocardiographic criteria, including (1) LV hypertrophy with deep endomyocardial trabeculations in
1 ventricular wall segments, (2) reduced LV
systolic function, and (3) presence or absence of LV dilation.
Cardiac structure was evaluated, and cardiac anomalies that exhibit a
similar myocardial pattern of persistent sinusoids, such as pulmonary
atresia, were excluded. After a proband was identified, a family
history was obtained, and all potentially informative family members
underwent physical examination, chest radiograph, ECG, and
echocardiogram. Stringent clinical criteria were used for diagnosis of BTHS in the probands. In all cases, the probands were required to have the following features: male infants, sporadic or X-linked inheritance, DCM or dilated hypertrophic cardiomyopathy, neutropenia, and 3-methylglutaconic aciduria. The clinical evaluation of each proband included physical examination and echocardiography (2D, M-mode, color Doppler) with evaluation of cardiac structure and with standard measurements of LV size, function (shortening fraction, ejection fraction), and valvular regurgitation. In addition, chest radiography, electrocardiography, urine organic acids, and complete blood count with differential were performed. Family members were screened by physical examination, chest radiograph, ECG, echocardiogram, urine organic acid analysis, and complete blood count with differential.
After informed consent, blood was obtained for the development of lymphoblastoid cell lines15 and DNA extraction by use of QIAamp DNA extraction kits. Age-, ethnicity-, and sex-matched negative control patients were recruited, and blood was obtained for DNA extraction after informed consent.
Single-Strand Conformational
Polymorphism Analysis
Mutation analysis was performed as previously
described.15 Primers were
designed to amplify the genes encoding G4.5
(Table 1
) and -dystrobrevin
(Table 2) in an exon-by-exon manner. Radioactive PCR was
performed as previously
described.15 In brief, after
a 5-minute denaturation step at 94°C, 35 cycles of amplification
(94°C for 30 seconds, X°C for 30 seconds, and 72°C for 20
seconds, where X represents the annealing temperature shown in the
respective Table) were performed. This was followed by a 72°C
incubation for 3 minutes. After PCR amplification, the samples were
denatured and analyzed by polyacrylamide gel electrophoresis and
autoradiography.15
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Sequence Analysis
Normal and aberrant single-strand conformational
polymorphism (SSCP) conformers from each exon were excised directly
from dried gels, purified, and sequenced according to the ABI Big Dye
Terminator Cycle Sequencing protocol and either an ABI 373 or ABI 310
Automated
Sequencer.15
BLAST search was used to identify homology between the sequences obtained from patients and to evaluate sequence conservation across species. Protein structural prediction was performed by the Garnier-Osguthorpe-Robson plot method.16
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Results |
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Patient Characteristics and Mutation Screening
LVNC With CHD
Family NLVNC-09 (Figure 1A
): A 4-generation Japanese family with 6 affected
individuals, including 5 with LVNC associated with CHD and 1
with isolated LVNC (proband III-2), was identified. The patients’ ages
ranged from 2 days to 69 years. All patients with CHD had 1 VSDs. In
1 child (IV-2), a patent ductus arteriosus was noted, and another child
(IV-3) was identified with a hypoplastic LV. One child (IV-1) died with
a hypoplastic left heart and hydrops fetalis diagnosed 2 days after
birth.
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Although the pattern of inheritance was determined to be autosomal dominant or mitochondrial, an X-linked pattern could not be completely excluded. For that reason, genetic screening for G4.5 mutations was undertaken. No mutations were found by either SSCP analysis or direct sequencing.
Mutation analysis of
-dystrobrevin identified an
abnormal SSCP conformer in affected members of NLVNC-9
(Figure 2A). Manual
(Figure 2B) and automated
(Figure 2C) sequencing identified a CT substitution at
position 362 of exon 3, resulting in an amino acid change from proline
to leucine at codon 121 (P121L,
Table 3). The unaffected members of this family did not
carry this mutation. Three hundred age- and sex-matched controls (200
Japanese, 100 white) were screened as well, and no mutations were
identified.
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Comparison of human and mouse
-dystrobrevin demonstrates this nucleotide (362)
and codon (121) to be conserved: there is >90% homology in this
region of the dystrobrevin gene. Protein sequence
analysis predicted that the amino acid substitution will result in the
reduction of an -helix by 2 amino acids and the removal of a loop in
this portion of the protein, which encodes the calcium-binding
EF-hand domain, possibly resulting in a significant secondary
structural change.
Family NLVNC-10: The
second family with LVNC with CHD
(Figure 1B
, NLVNC-10) was also identified in Japan. This
2-generation family includes 3 affected individuals; in 2 patients
(including the proband I-2), an associated atrial septal defect was
identified (I-2 and II-2), and the other patient had a small VSD that
closed spontaneously (II-3). All affected patients were female, and all
are alive. The pattern of inheritance is autosomal dominant or
mitochondrial. No mutations in
-dystrobrevin or
G4.5 were found in NLVNC-10,
suggesting genetic heterogeneity in LVNC associated with
CHD.
Sporadic cases: In
the 3 sporadic cases from the United States, all children presented
with LVNC early in life (1 week, 3 weeks, 2 months); 2 were female and
1 male. In all 3 patients, a VSD was identified. The male child also
had pulmonic stenosis. All are still alive. No mutations in
-dystrobrevin or
G4.5 were
found.
Isolated LVNC
Family BSG
(Figure 1C): This family consisted of a 33-year-old mother
and 26-year-old father; there were no children other than the
5-month-old male proband with isolated LVNC associated with a dilated,
mildly hypertrophic heart
(Figure 3), with poor systolic function on echocardiogram and
clinical heart failure. Neutropenia and 3-methylglutaconic aciduria
were also identified. Maternal family history was notable for 1 sibling
(healthy sister) and no family history of heart disease or hematologic
disease. The mother’s echocardiogram was normal.
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SSCP screening of
G4.5 with exon 4 primers
identified an abnormal conformer in the affected child and carrier
mother. DNA sequence analysis demonstrated a TC missense
substitution at nucleotide 352
(Table 3), which resulted in an amino acid change from
cysteine to arginine at codon 118 (C118R).
Family BSL
(Figure 1D): This Vietnamese family included a 23-year-old
mother and 26-year-old father. The proband was the only child born to
this couple, and he presented in heart failure in infancy. An
echocardiogram demonstrated a severely dilated LV with deep
trabeculations consistent with isolated LVNC, and systolic function was
poor; neutropenia and 3-methylglutaconic aciduria were also identified.
The child’s mother was adopted, and therefore no family history was
available. Her health was good, with no evidence of heart disease, and
her echocardiogram was normal.
SSCP analysis using primers for exon 10 of
G4.5 identified an abnormal
conformer in the proband and his mother. DNA sequence analysis
identified a TA substitution at the intron 10 splice donor site
(IVS10+2TA,
Table 3).
Dilated Cardiomyopathy with BTHS
Family BSH
(Figure 1E): This infant boy (3 months) presented with signs
and symptoms of congestive heart failure and low cardiac output. The
echocardiogram demonstrated hypertrophic dilated cardiomyopathy with
severely reduced LV function. Neutropenia and 3-methylglutaconic
aciduria were also identified. Evaluation of family members identified
2 other male children, previously diagnosed with pure DCM by
echocardiography in infancy, who had died suddenly with DCM and heart
failure. The parents were in good health, and the mother’s family
history was negative for heart disease or sudden death. Her
echocardiogram was normal. She had 2 sisters who were clinically
well.
Using primers for exon 2 of
G4.5, SSCP analysis identified
an abnormal conformer in affected and carrier individuals. Sequence
analysis demonstrated a deletion of cytosine (TCCATCA) at nucleotide
123 (codon 41), resulting in a frameshift that changed codon 42 from a
leucine to a premature stop codon, thereby truncating the protein
product
(Table 3).
Family BSD
(Figure 1F): The proband was a 15-year-old diagnosed with
signs and symptoms of congestive heart failure and low cardiac output.
Echocardiograms demonstrated LV dilation and severely reduced LV
function. The members of this family were screened by echocardiography,
which allowed identification of multiple affected males, including 2
infants
(Figure 1F, III-3, III-4). For this reason, all patients were
screened for organic aciduria and metabolic derangements. These studies
identified lactic acidosis in 2 children
(Figure 1F, III-2, III-7), cyclic neutropenia in 3
individuals
(Figure 1F, III-3, III-4, III-7), and 3-methylglutaconic
aciduria in 2 children
(Figure 1F, III-4, III-7). In 2 children, protein-C
deficiency was diagnosed
(Figure 1F, III-3, III-4). The members of this family had
diagnoses ranging from classic BTHS to fatal infantile DCM to
late-onset symptomatic and asymptomatic DCM.
An abnormal conformer in exon 2 of
G4.5 was also detected in this
proband
(Figure 4A). DNA sequence analysis demonstrated an AG
substitution at the splice acceptor site (398-2 AG) of exon 2
(Figure 4B and 4C). Subsequently, SSCP and sequence analysis
of extended family members demonstrated the identical mutation in males
with DCM (with or without metabolic abnormalities,
Table 3) and female carriers.
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None of these G4.5 mutations were identified in 200 control patient samples.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Over the past few years, our understanding of the molecular basis of DCM has increased considerably, with the description of mutations in several of the structural proteins, including dystrophin,17 lamin A/C,18 desmin,19 cardiac actin,14 and
-sarcoglycan.20 In
addition, mutations have been described in the gene
G4.5 in patients with classic
BTHS,5 21 as well
as in patients with infantile
DCM8 and isolated
LVNC.4 Here, we report the
identification of novel mutations in
G4.5 in patients with isolated
LVNC. In patients with LVNC associated with CHD, however, no mutations
were identified in G4.5.
Instead, we identified a mutation in the calcium-binding EF-hand domain
of -dystrobrevin in 1
family.
The -dystrobrevin
gene is alternatively spliced, resulting in multiple isoforms of
dystrobrevin (, ß, 
), with different tissue
distributions,22 of which
only -dystrobrevin is
expressed in the heart. -Dystrobrevin is a member of the DAPC, which
is composed of 3 subcomplexes: the dystroglycan complex, the
sarcoglycan complex, and the cytoplasmic complex, which includes the
syntrophins and
dystrobrevins.23 The DAPC,
which is located at the sarcolemma, connects the cysteine-rich and
C-terminal domains of dystrophin with ß-dystroglycan and the
cytoplasmic complex, respectively. ß-Dystroglycan is a transmembrane
protein that binds to the laminin-binding protein -dystroglycan in
the extracellular matrix.24
At the N-terminus, dystrophin binds to actin. These interactions
effectively link the extracellular matrix to the dystrophin-based
cytoskeleton of the muscle fiber at the C-terminus and to the
contractile apparatus at the N-terminus. Furthermore, -dystrobrevin
links the DAPC to the signaling protein neuronal nitric oxide synthase
(nNOS).25 Disruption of
these links results in severe muscle wasting or cardiac muscle
pathology.11 26
For example, dystrophin
mutations cause Duchenne muscular
dystrophy27 or X-linked
dilated cardiomyopathy,17
whereas mutations in actin have
been shown to cause either DCM or hypertrophic
cardiomyopathy,14 28
and mutations in -sarcoglycan result in limb-girdle
muscular dystrophy29 or
DCM.20 Mutations in
-dystrobrevin have been
shown to result in muscular dystrophy in
humans30 and have also been
found to cause skeletal myopathy and cardiomyopathy in
mice.31 Of particular
interest is the description by Grady and
colleagues32 of a mouse
deficient in -dystrobrevin, derived by homozygous deletion of exon
3, where reduced signaling via nNOS results in skeletal and cardiac
(degenerating myocytes, mononuclear cell infiltration, and fibrosis)
myopathies. These data suggest that the region of the gene encoded by
exon 3, the same region as mutated in the patient described here, is
essential for functionality of the protein. We are in the process of
generating transgenic mice to confirm that the mutation identified in
this patient is disease-causing.
The -dystrobrevin
mutation described here results in a phenotype of dilated hypertrophic
cardiomyopathy with deep trabeculations, associated with congenital
heart disease, consistent with the criteria for LVNC. There is
considerable variability in disease development in this family,
however, with congenital disease ranging in severity from a simple VSD
to hypoplastic left heart syndrome; in 1 patient, isolated LVNC without
CHD was also notable. Several mechanisms could account for these
observations, including environmental factors and acquired traits, as
well as the existence of modifier genes and polymorphisms that could
modulate phenotypic
expression.33 34
For example, for the ACE insertion/deletion (ACE I/D) polymorphism, the
D allele in patients with hypertrophic cardiomyopathy is associated
with a high incidence of sudden
death.33 It is also likely
that the various forms of CHD occur because of alterations in the
signaling pathways that -dystrobrevin participates in, including the
interactions with the NOS and transforming growth factor-ß pathways.
It has been well described previously that transcription factor
abnormalities can cause
CHD,35 and the forms of CHD
may be quite variable, as occurs with heterotaxy syndrome, with wide
differences in severity. Although it is unclear at present what
specific mechanism is involved, we would suggest that perturbations in
these pathways lead to developmental errors that are dependent on
genetic background and developmental timing. Because myocardial
development occurs very early in human development, a variety of
interactions later in development are likely to modify the results of
the initial insult.
The novel mutations identified in G4.5 in patients with LVNC or BTHS and in patients with relatively late-onset DCM included nonsense and missense mutations. Several important points are now becoming apparent with regard to G4.5 mutations. First, many affected individuals develop severe infantile disease and succumb. The gene defect usually differs among families, however, and thus far there do not appear to be obvious genotype:phenotype correlations that allow the differentiation of clinical course to be predicted. Second, the cardiac phenotypes that occur as a result of G4.5 mutations may vary significantly. The cardiac manifestations include DCM, endocardial fibroelastosis, LVNC, and dilated hypertrophic cardiomyopathy. In addition, this phenotype can differ among family members and change over time, possibly in response to therapy. Finally, the systemic manifestations of BTHS are equally unpredictable. In some children, sudden death occurs. It is likely that modifier genes are involved in determining the phenotype and clinical severity.
We suggest that studies of patients with myocardial disorders having prominent systolic dysfunction should include evaluation of members of the cytoskeleton-sarcolemma complex, as well as G4.5, as candidate genes, and when associated with CHD, signaling pathways/transcription factors should be targeted as well.
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Acknowledgments |
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This work was supported by grants from the Abercrombie Cardiology Fund of Texas Children’s Hospital, the Texas Children’s Hospital Foundation Chair in Pediatric Cardiovascular Research, the American Heart Association (Texas Affiliate and National Center), the Howard Hughes Medical Institute, the National Institutes of Health, National Heart, Lung, and Blood Institute, and the Japanese Ministry of Education, Science, and Culture. Fukiko Ichida, MD, is supported by grants from the Ministry of Education, Science, and Culture in Japan. Neil E. Bowles, PhD, is supported by a grant from the American Heart Association, Texas Affiliate, and by the Abercrombie Cardiology Fund of Texas Children’s Hospital. Karla R. Bowles, PhD, is a Howard Hughes Medical Institute Predoctoral Fellow. William J. Dreyer, MD, is supported by grants from the American Heart Association, National Center, and by the Abercrombie Cardiology Fund of Texas Children’s Hospital. Jeffrey A. Towbin, MD, is supported by the Texas Children’s Hospital Foundation Chair in Pediatric Cardiovascular Research and by grants from the National Institutes of Health, National Heart, Lung, and Blood Institute. The authors are grateful to Drs Yasuo Ono, Teiji Akagi, Toshiharu Miyake, Hiromichi Hamada, Masaru Terai, Hiroshi Mito, Yasuo Murakami, Takehiko Ishida, Masaki Nii, Yasuhiko Tanaka, Tohru Matsushita, Takeshi Isobe, Hiroshi Sugiyama, Hitoshi Horigome, and Masayuki Matsumoto for patient referrals; Melba Koegele and Kristin Chapman for expert technical assistance; and Dr Partha Sen for the DNA sequence analysis.
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Footnotes |
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Drs Ichida and Tsubata and Drs N.E. Bowles and Towbin contributed equally to this work.
Guest Editor for this article was Christine E. Seidman, MD, Harvard Medical School, Boston, Mass.
Received July 7, 2000; revision received October 24, 2001; accepted November 3, 2000.
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References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. Dusek J, Ostadal B, Duskova M. Postnatal persistence of spongy myocardium with embryonic blood supply. Arch Pathol. 1975;99:312–317.[Medline] [Order article via Infotrieve]
2.
Chin TK, Perloff
JK, Williams RG, et al. Isolated noncompaction of left ventricular
myocardium: a study of eight cases.
Circulation. 1990;82:507–513.
3.
Ichida F, Hamamichi
Y, Miyawaki T, et al. Clinical features of isolated noncompaction of
the ventricular myocardium: long-term clinical course, hemodynamic
properties, and genetic background. J
Am Coll Cardiol. 1999;34:233–240.
4. Bleyl SB, Mumford BR, Thompson V, et al. Neonatal, lethal noncompaction of the left ventricular myocardium is allelic with Barth syndrome. Am J Hum Genet. 1997;61:868–872.[Medline] [Order article via Infotrieve]
5. Bione S, D’Adamo P, Maestrini E, et al. A novel X-linked gene, G4.5, is responsible for Barth syndrome. Nat Genet. 1996;12:385–389.[Medline] [Order article via Infotrieve]
6.
Neustein HB, Lurie
PR, Dahms B, et al. An X-linked recessive cardiomyopathy with abnormal
mitochondria. Pediatrics. 1979;64:24–29.
7. Barth PG, Scholte HR, Berden JA, et al. An X-linked mitochondrial disease affecting cardiac muscle, skeletal muscle and neutrophil leucocytes. J Neurol Sci. 1983;62:327–355.[Medline] [Order article via Infotrieve]
8. D’Adamo P, Fassone L, Gedeon A, et al. The X-linked gene G4.5 is responsible for different infantile dilated cardiomyopathies. Am J Hum Genet. 1997;61:862–867.[Medline] [Order article via Infotrieve]
9.
Gedeon AK, Wilson
MJ, Colley AC, et al. X linked fatal infantile cardiomyopathy maps to
Xq28 and is possibly allelic to Barth syndrome.
J Med Genet. 1995;32:383–388.
10. Grady RM, Teng H, Nichol MC, et al. Skeletal and cardiac myopathies in mice lacking utrophin and dystrophin: a model for Duchenne muscular dystrophy. Cell. 1997;90:729–738.[Medline] [Order article via Infotrieve]
11. Hoffman EP, Clemens PR. HyperCKemic, proximal muscular dystrophies and the dystrophin membrane cytoskeleton, including dystrophinopathies, sarcoglycanopathies, and merosinopathies. Curr Opin Rheumatol. 1996;8:528–538.[Medline] [Order article via Infotrieve]
12.
Sakamoto A, Ono
K, Abe M, et al. Both hypertrophic and dilated cardiomyopathies are
caused by mutation of the same gene, delta-sarcoglycan, in hamster: an
animal model of disrupted dystrophin-associated glycoprotein complex.
Proc Natl Acad Sci
U S A. 1997;94:13873–13878.
13. Arber S, Hunter JJ, Ross J Jr, et al. MLP-deficient mice exhibit a disruption of cardiac cytoarchitectural organization, dilated cardiomyopathy, and heart failure. Cell. 1997;88:393–403.[Medline] [Order article via Infotrieve]
14.
Olson TM, Michels
VV, Thibodeau SN, et al. Actin mutations in dilated cardiomyopathy, a
heritable form of heart failure.
Science. 1998;280:750–752.
15.
Li H, Chen Q,
Moss AJ, et al. New mutations in the KVLQT1 potassium channel that
cause long-QT syndrome.
Circulation. 1998;97:1264–1269.
16. Garnier J, Osguthorpe DJ, Robson B. Analysis of the accuracy and implications of simple methods for predicting the secondary structure of globular proteins. J Mol Biol. 1978;120:97–120.[Medline] [Order article via Infotrieve]
17.
Muntoni F, Cau M,
Ganau A, et al. Brief report: deletion of the dystrophin
muscle-promoter region associated with X-linked dilated cardiomyopathy.
N Engl J Med. 1993;329:921–925.
18.
Fatkin D, MacRae
C, Sasaki T, et al. Missense mutations in the rod domain of the lamin
A/C gene as causes of dilated cardiomyopathy and conduction-system
disease. N Engl J
Med. 1999;341:1715–1724.
19.
Li D, Tapscoft T,
Gonzalez O, et al. Desmin mutation responsible for idiopathic dilated
cardiomyopathy. Circulation. 1999;100:461–464.
20. Tsubata S, Bowles KR, Vatta M, et al. Mutations in the human delta-sarcoglycan gene in familial and sporadic dilated cardiomyopathy. J Clin Invest.. 2000;106:655–662.[Medline] [Order article via Infotrieve]
21. Johnston J, Kelley RI, Feigenbaum A, et al. Mutation characterization and genotype-phenotype correlation in Barth syndrome. Am J Hum Genet. 1997;61:1053–1058.[Medline] [Order article via Infotrieve]
22.
Blake DJ,
Nawrotzki R, Peters MF, et al. Isoform diversity of dystrobrevin, the
murine 87-kDa postsynaptic protein. J
Biol Chem. 1996;271:7802–7810.
23. Chen J, Chien KR. Complexity in simplicity: monogenic disorders and complex cardiomyopathies. J Clin Invest. 1999;103:1483–1485.[Medline] [Order article via Infotrieve]
24. Campbell KP, Kahl SD. Association of dystrophin and an integral membrane glycoprotein. Nature. 1989;338:259–262.[Medline] [Order article via Infotrieve]
25.
Yoshida M, Hama
H, Ishikawa-Sakurai M, et al. Biochemical evidence for association of
dystrobrevin with the sarcoglycan-sarcospan complex as a basis for
understanding sarcoglycanopathy. Hum Mol
Genet. 2000;9:1033–1040.
26. Hoffman EP. Clinical and histopathological features of abnormalities of the dystrophin-based membrane cytoskeleton. Brain Pathol. 1996;6:49–61.[Medline] [Order article via Infotrieve]
27. Hoffman EP, Brown RH Jr, Kunkel LM. Dystrophin: the protein product of the Duchenne muscular dystrophy locus. Cell. 1987;51:919–928.[Medline] [Order article via Infotrieve]
28. Mogensen J, Klausen IC, Pedersen AK, et al. Alpha-cardiac actin is a novel disease gene in familial hypertrophic cardiomyopathy. J Clin Invest. 1999;103:R39–R43.
29. Nigro V, de Sa Moreira E, Piluso G, et al. Autosomal recessive limb-girdle muscular dystrophy, LGMD2F, is caused by a mutation in the delta-sarcoglycan gene. Nat Genet. 1996;14:195–198.[Medline] [Order article via Infotrieve]
30.
Metzinger L,
Blake DJ, Squier MV, et al. Dystrobrevin deficiency at the sarcolemma
of patients with muscular dystrophy. Hum
Mol Genet. 1997;6:1185–1191.
31. Sanes JR, Apel ED, Burgess RW, et al. Development of the neuromuscular junction: genetic analysis in mice. J Physiol Paris. 1998;92:167–172.[Medline] [Order article via Infotrieve]
32. Grady RM, Grange RW, Lau KS, et al. Role for alpha-dystrobrevin in the pathogenesis of dystrophin-dependent muscular dystrophies. Nat Cell Biol. 1999;1:215–220.[Medline] [Order article via Infotrieve]
33. Marian AJ, Yu QT, Workman R, et al. Angiotensin-converting enzyme polymorphism in hypertrophic cardiomyopathy and sudden cardiac death. Lancet. 1993;342:1085–1086.[Medline] [Order article via Infotrieve]
34. Brugada R, Kelsey W, Lechin M, et al. Role of candidate modifier genes on the phenotypic expression of hypertrophy in patients with hypertrophic cardiomyopathy. J Invest Med. 1997;45:542–551.[Medline] [Order article via Infotrieve]
35. Srivastava D. Developmental and genetic aspects of congenital heart disease. Curr Opin Cardiol. 1999;14:263–268.[Medline] [Order article via Infotrieve]
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 |
|
 J. M. Bos, J. A. Towbin, and M. J. Ackerman Diagnostic, prognostic, and therapeutic implications of genetic testing for hypertrophic cardiomyopathy. J. Am. Coll. Cardiol., July 14, 2009; 54(3): 201 - 211. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. B. Gelberg Purkinje Fiber Dysplasia (Histiocytoid Cardiomyopathy) with Ventricular Noncompaction in a Savannah Kitten Vet. Pathol., July 1, 2009; 46(4): 693 - 697. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Nakano, H. Nakano, and K.R. Chien Multipotent Islet-1 Cardiovascular Progenitors in Development and Disease Cold Spring Harb Symp Quant Biol, February 9, 2009; (2009) sqb.2008.73.055v1. [Abstract] [PDF]
|
|
|
|
 |
|
 F P JUNQUEIRA, F D B FERNANDES, A C COUTINHO, P V DE PONTES, and R C DOMINGUES Isolated left ventricular myocardium non-compaction: MR imaging findings from three cases Br. J. Radiol., February 1, 2009; 82(974): e37 - e41. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. G. Priori, C. Napolitano, S. E. Humphries, and J. Skipworth CHAPTER 9 Genetics of Cardiovascular Diseases ESC Textbook of Cardiovascular Medicine, January 1, 2009; 2(1): med-9780199566990-chapter - med-9780199566990-chapter. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
O. M. Hess, W. McKenna, and H.-P. Schultheiss CHAPTER 18 Myocardial Disease ESC Textbook of Cardiovascular Medicine, January 1, 2009; 2(1): med-9780199566990-chapter - med-9780199566990-chapter. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. M. Boe, L. Rhee-Morris, D. Towner, and A. J. Moon-Grady Prenatal Diagnosis of Omphalocele and Left Atrial Isomerism (Polysplenia) Including Complex Congenital Heart Disease With Ventricular Noncompaction Cardiomyopathy J. Ultrasound Med., July 1, 2008; 27(7): 1117 - 1121. [Full Text] [PDF]
|
|
|
|
 |
|
 S. Klaassen, S. Probst, E. Oechslin, B. Gerull, G. Krings, P. Schuler, M. Greutmann, D. Hurlimann, M. Yegitbasi, L. Pons, et al. Mutations in Sarcomere Protein Genes in Left Ventricular Noncompaction Circulation, June 3, 2008; 117(22): 2893 - 2901. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Tatu-Chitoiu and S. Bradisteanu A rare case of biventricular non-compaction associated with ventricular septal defect and descendent aortic stenosis in a young man Eur J Echocardiogr, March 1, 2008; 9(2): 306 - 308. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Nakamori, T. Kimura, T. Kubota, T. Matsumura, H. Sumi, H. Fujimura, M. P. Takahashi, and S. Sakoda Aberrantly spliced {alpha}-dystrobrevin alters {alpha}-syntrophin binding in myotonic dystrophy type 1 Neurology, February 26, 2008; 70(9): 677 - 685. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. K. Kohli, A. A. Pantazis, J. S. Shah, B. Adeyemi, G. Jackson, W. J. McKenna, S. Sharma, and P. M. Elliott Diagnosis of left-ventricular non-compaction in patients with left-ventricular systolic dysfunction: time for a reappraisal of diagnostic criteria? Eur. Heart J., January 1, 2008; 29(1): 89 - 95. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. M. Hoedemaekers, K. Caliskan, D. Majoor-Krakauer, I. van de Laar, M. Michels, M. Witsenburg, F. J. ten Cate, M. L. Simoons, and D. Dooijes Cardiac {beta}-myosin heavy chain defects in two families with non-compaction cardiomyopathy: linking non-compaction to hypertrophic, restrictive, and dilated cardiomyopathies Eur. Heart J., November 2, 2007; 28(22): 2732 - 2737. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. H. Robin, P. B. Tabereaux, R. Benza, and B. R. Korf Genetic Testing in Cardiovascular Disease J. Am. Coll. Cardiol., August 21, 2007; 50(8): 727 - 737. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Monserrat, M. Hermida-Prieto, X. Fernandez, I. Rodriguez, C. Dumont, L. Cazon, M. G. Cuesta, C. Gonzalez-Juanatey, J. Peteiro, N. Alvarez, et al. Mutation in the alpha-cardiac actin gene associated with apical hypertrophic cardiomyopathy, left ventricular non-compaction, and septal defects Eur. Heart J., August 2, 2007; 28(16): 1953 - 1961. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 U. Philipp, C. Broschk, A. Vollmar, and O. Distl Evaluation of Tafazzin as Candidate for Dilated Cardiomyopathy in Irish Wolfhounds J. Hered., July 9, 2007; (2007) esm045v1. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Lorsheyd, M.-J. M. Cramer, B. K. Velthuis, E.-J. P. Vonken, J. van der Smagt, P. van Tintelen, and R. N.W. Hauer Familial occurrence of isolated non-compaction cardiomyopathy Eur J Heart Fail, December 1, 2006; 8(8): 826 - 831. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. E. Ulusoy, N. Kucukarslan, A. Kirilmaz, and E. Demiralp Noncompaction of ventricular myocardium involving both ventricles Eur J Echocardiogr, December 1, 2006; 7(6): 457 - 460. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Markiewicz-Loskot, E. Moric-Janiszewska, M. Loskot, L. Szydlowski, L. Weglarz, and A. Hollek Isolated ventricular non-compaction: clinical study and genetic review Europace, December 1, 2006; 8(12): 1064 - 1067. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. A. Towbin, A. M. Lowe, S. D. Colan, L. A. Sleeper, E. J. Orav, S. Clunie, J. Messere, G. F. Cox, P. R. Lurie, D. Hsu, et al. Incidence, causes, and outcomes of dilated cardiomyopathy in children. JAMA, October 18, 2006; 296(15): 1867 - 1876. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C Stollberger and J Finsterer Pitfalls in the diagnosis of left ventricular hypertrabeculation/non-compaction. Postgrad. Med. J., October 1, 2006; 82(972): 679 - 683. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Lilje, V. Razek, J. J. Joyce, T. Rau, B. F. Finckh, F. Weiss, C. R. Habermann, J. C. Rice, and J. Weil Complications of non-compaction of the left ventricular myocardium in a paediatric population: a prospective study Eur. Heart J., August 1, 2006; 27(15): 1855 - 1860. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Aras, O. Tufekcioglu, S. Topaloglu, K. Ergun, O. Ozeke, A. Yildiz, and S. Korkmaz Response Eur J Echocardiogr, January 1, 2006; 7(1): 7 - 8. [Full Text] [PDF]
|
|
|
|
|
|
R. T. Murphy, R. Thaman, J. G. Blanes, D. Ward, E. Sevdalis, E. Papra, A. Kiotsekolglou, M. T. Tome, D. Pellerin, W. J. McKenna, et al. Natural history and familial characteristics of isolated left ventricular non-compaction Eur. Heart J., January 2, 2005; 26(2): 187 - 192. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Stollberger and J. Finsterer Cardiologic and neurologic findings in left ventricular hypertrabeculation/non-compaction related to wall thickness, size and systolic function Eur J Heart Fail, January 1, 2005; 7(1): 95 - 97. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. Gorgulu, S. Celik, A. Eksik, and T. Tezel Double-Orifice Mitral Valve Associated with Nonisolated Left Ventricular Noncompaction: A Case Report Angiology, November 1, 2004; 55(6): 707 - 710. [Abstract] [PDF]
|
|
|
|
|
|
B. C. Weiford, V. D. Subbarao, and K. M. Mulhern Noncompaction of the Ventricular Myocardium Circulation, June 22, 2004; 109(24): 2965 - 2971. [Full Text] [PDF]
|
|
|
|
|
|
S. Sasse-Klaassen, S. Probst, B. Gerull, E. Oechslin, P. Nurnberg, A. Heuser, R. Jenni, H. C. Hennies, and L. Thierfelder Novel Gene Locus for Autosomal Dominant Left Ventricular Noncompaction Maps to Chromosome 11p15 Circulation, June 8, 2004; 109(22): 2720 - 2723. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Chen, S. Shi, L. Acosta, W. Li, J. Lu, S. Bao, Z. Chen, Z. Yang, M. D. Schneider, K. R. Chien, et al. BMP10 is essential for maintaining cardiac growth during murine cardiogenesis Development, May 1, 2004; 131(9): 2219 - 2231. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. A. Lapidos, R. Kakkar, and E. M. McNally The Dystrophin Glycoprotein Complex: Signaling Strength and Integrity for the Sarcolemma Circ. Res., April 30, 2004; 94(8): 1023 - 1031. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Finsterer, C. Stollberger, G. Blazek, R. Pignatelli, C. J. McMahon, W. J. Dreyer, S. W. Denfield, J. Wu, J. Price, H. El Said, et al. Left Ventricular Noncompaction Suggests Myopathy * Response Circulation, April 27, 2004; 109(16): e201 - e202. [Full Text] [PDF]
|
|
|
|
 |
|
 D. E. Albrecht and S. C. Froehner DAMAGE, a Novel {alpha}-Dystrobrevin-associated MAGE Protein in Dystrophin Complexes J. Biol. Chem., February 20, 2004; 279(8): 7014 - 7023. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Schlame, R. I. Kelley, A. Feigenbaum, J. A. Towbin, P. M. Heerdt, T. Schieble, R. J. A. Wanders, S. DiMauro, and T. J. J. Blanck Phospholipid abnormalities in children with Barth syndrome J. Am. Coll. Cardiol., December 3, 2003; 42(11): 1994 - 1999. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Vatta, B. Mohapatra, S. Jimenez, X. Sanchez, G. Faulkner, Z. Perles, G. Sinagra, J.-H. Lin, T. M. Vu, Q. Zhou, et al. Mutations in Cypher/ZASP in patients with dilated cardiomyopathy and left ventricular non-compaction J. Am. Coll. Cardiol., December 3, 2003; 42(11): 2014 - 2027. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. H. Pignatelli, C. J. McMahon, W. J. Dreyer, S. W. Denfield, J. Price, J. W. Belmont, W. J. Craigen, J. Wu, H. El Said, L. I. Bezold, et al. Clinical Characterization of Left Ventricular Noncompaction in Children: A Relatively Common Form of Cardiomyopathy Circulation, November 25, 2003; 108(21): 2672 - 2678. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. M. Vaz, R. H. Houtkooper, F. Valianpour, P. G. Barth, and R. J. A. Wanders Only One Splice Variant of the Human TAZ Gene Encodes a Functional Protein with a Role in Cardiolipin Metabolism J. Biol. Chem., October 31, 2003; 278(44): 43089 - 43094. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Mogensen, A. Bahl, and W. J McKenna Hypertrophic cardiomyopathy--the clinical challenge of managing a hereditary heart condition Eur. Heart J., March 2, 2003; 24(6): 496 - 498. [Full Text] [PDF]
|
|
|
|
|
|
I. A. Khan, W. P. Biddle, S. A. Najeed, S. Abdul-Aziz, N. J. Mehta, V. Salaria, A. L. Murcek, and D. M. Harris Isolated Noncompaction Cardiomyopathy Presenting with Paroxysmal Supraventricular Tachycardia: Case Report and Literature Review Angiology, March 1, 2003; 54(2): 243 - 250. [Abstract] [PDF]
|
|
|
|
 |
|
 D. L. Brutsaert Cardiac Endothelial-Myocardial Signaling: Its Role in Cardiac Growth, Contractile Performance, and Rhythmicity Physiol Rev, January 1, 2003; 83(1): 59 - 115. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N.E. Bowles The molecular biology of dilated cardiomyopathy Eur. Heart J. Suppl., December 1, 2002; 4(suppl_I): I2 - I7. [Abstract] [PDF]
|
|
|
|
|
|
J. Feng, J. Yan, C. H. Buzin, S. S. Sommer, and J. A. Towbin Comprehensive mutation scanning of the dystrophin gene in patients with nonsyndromic X-linked dilated cardiomyopathy J. Am. Coll. Cardiol., September 18, 2002; 40(6): 1120 - 1124. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J.-J. Hwang, P. D. Allen, G. C. Tseng, C.-W. Lam, L. Fananapazir, V. J. Dzau, and C.-C. Liew Microarray gene expression profiles in dilated and hypertrophic cardiomyopathic end-stage heart failure Physiol Genomics, July 12, 2002; 10(1): 31 - 44. [Abstract] [Full Text] [PDF]
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