Novel Gene Mutations in Patients With Left Ventricular Noncompaction or Barth Syndrome

Ichida, Fukiko; Tsubata, Shinichi; Bowles, Karla R.; Haneda, Noriyuki; Uese, Keiichiro; Miyawaki, Toshio; Dreyer, William J.; Messina, John; Li, Hua; Bowles, Neil E.; Towbin, Jeffrey A.

doi:10.1161/01.cir.103.9.1256

Cited by 507 publications

(369 citation statements)

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“…lished missense mutations, 7 occur in these motifs. Mutations V183G and G197E have been found repeatedly (Bleyl et al, 1997;Cantlay et al, 1999;D'Adamo et al, 1997;Ichida et al, 2001;Johnston et al, 1997;Neuwald, 1997). The significant clustering of over one-half the reported disease-causing mutations in putative acyltransferase motifs (p Ͻ 0.022, 2 test) may reveal regions of the tafazzin protein critical for its function.…”

Section: Mutations In Gene G45mentioning

confidence: 99%

Infantile Dilated X-Linked Cardiomyopathy, G4.5 Mutations, Altered Lipids, and Ultrastructural Malformations of Mitochondria in Heart, Liver, and Skeletal Muscle

Bissler

Tsoras

Göring

et al. 2002

Laboratory Investigation

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SUMMARY:Mutations in the Xq28 gene G4.5 lead to dilated cardiomyopathy (DCM). Differential splicing of G4.5 results in a family of proteins called "tafazzins" with homology to acyltransferases. These enzymes assemble fatty acids into membrane lipids. We sequenced G4.5 in two kindreds with X-linked DCM and in two unrelated men, one with idiopathic DCM and the other with DCM of arrhythmogenic right ventricular dysplasia. We examined the ultrastructure of heart, liver, and muscle biopsy specimens in these three DCM types; we used gas chromatography to compare fatty acid composition in heart, liver, and muscle autopsy specimens of two patients of kindred 1 with that of controls. In X-linked DCM, G4.5 had a stop codon (E188X), a nonsense mutation, in kindred 1 and an amino acid substitution (G240R), a missense mutation, in kindred 2. In the two men with isolated DCM, G4.5 was not mutated. Ultrastructural mitochondrial malformations were present in the biopsy tissues of the patients with DCM. Cardiac biopsy specimens of both kindreds with X-linked DCM exhibited greatly enlarged mitochondria with large bundles of stacked, compacted, disarrayed cristae that differed from those of the two types of isolated DCM. Autopsy tissue of patients with X-linked DCM had decreased unsaturated and increased saturated fatty acid concentrations. Seven of 13 published G4.5 missense mutations, including the one presented here, occur in acyltransferase motifs. Impaired acyltransferase function could result in increased fatty acid saturation that would decrease membrane fluidity. Mitochondrial membrane proliferation may be an attempt to compensate for impaired function of acyltransferase. Cardiac ultrastructure separates X-linked DCM with G4.5 mutations from the two types of isolated DCM without G4.5 mutations. Electron microscopy of promptly fixed myocardial biopsy specimens has a role in defining the differential diagnosis of DCM. Mutational analysis of the G4.5 gene also serves this purpose. (Lab Invest 2002, 82:335-344).

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Section: Mutations In Gene G45mentioning

confidence: 99%

Infantile Dilated X-Linked Cardiomyopathy, G4.5 Mutations, Altered Lipids, and Ultrastructural Malformations of Mitochondria in Heart, Liver, and Skeletal Muscle

Bissler

Tsoras

Göring

et al. 2002

Laboratory Investigation

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“…There were also four families with co‐existing LVNC and DCM, and two families showed LVNC and HCM, and one family exhibited LVNC and a congenital heart defect (Ichida et al. 2001). Notably, we found two cases with several types of cardiac diseases in their families (Postma et al.…”

Section: Resultsmentioning

confidence: 99%

“…In all of these variants, there was family co‐segregation with the same phenotype (LVNC) (Ichida et al. 2001; Hoedemaekers et al. 2010; Esposito et al.…”

Section: Discussionmentioning

confidence: 99%

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The pathogenicity of genetic variants previously associated with left ventricular non‐compaction

Abbasi

Jabbari

et al. 2015

Molec Gen & Gen Med

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BackgroundLeft ventricular non‐compaction (LVNC) is a rare cardiomyopathy. Many genetic variants have been associated with LVNC. However, the number of the previous LVNC‐associated variants that are common in the background population remains unknown. The aim of this study was to provide an updated list of previously reported LVNC‐associated variants with biologic description and investigate the prevalence of LVNC variants in healthy general population to find false‐positive LVNC‐associated variants.Methods and ResultsThe Human Gene Mutation Database and PubMed were systematically searched to identify all previously reported LVNC‐associated variants. Thereafter, the Exome Sequencing Project (ESP) and the Exome Aggregation Consortium (ExAC), that both represent the background population, was searched for all variants. Four in silico prediction tools were assessed to determine the functional effects of these variants. The prediction results of those identified in the ESP and ExAC and those not identified in the ESP and ExAC were compared. In 12 genes, 60 LVNC‐associated missense/nonsense variants were identified. MYH7 was the predominant gene, encompassing 24 of the 60 LVNC‐associated variants. The ESP only harbored nine and ExAC harbored 18 of the 60 LVNC‐associated variants. In total, eight out of nine ESP‐positive variants overlapped with the 18 variants identified in ExAC database.ConclusionsIn this article, we identified 9 ESP‐positive and 18 ExAC‐positive variants of 60 previously reported LVNC‐associated variants, suggesting that these variants are not necessarily the monogenic cause of LVNC.

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“…It has been linked to mutations in several genes, including LIM domain-binding protein 3 (LDP3), dystrobrevin-α (DTNA), tafazzin/protein G4.5 (TAZ/G4.5), laminin A/C (LMNA), and genes encoding sarcomeric proteins such as myosin heavy chain 7 (MYH7), actin-α cardiac muscle 1 (ACTC1), and troponin T type 2 (TNNT2) (Ichida et al 1999(Ichida et al , 2001Klaassen et al 2008). Two forms of LVNC have been described: isolated LVNC in the absence of other cardiac anomalies, and non-isolated LVNC associated with congenital heart disease (Chin et al 1990).…”

mentioning

confidence: 99%

Surgical Repair of Left Ventricular Noncompaction in a Patient with a Novel Mutation of the Myosin Heavy Chain 7 Gene

Uchiyama¹,

Yoshimura²,

Kaneko³

et al. 2012

Tohoku J. Exp. Med.

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Left ventricular noncompaction (LVNC) represents arrest of the normal myocardial compaction process and results in the persistence of multiple prominent ventricular trabeculations and deep intertrabecular recesses. LVNC can be classified into 2 forms: isolated LVNC in the absence of other cardiac anomalies and non-isolated LVNC associated with congenital heart disease. The clinical presentation and the natural history of LVNC are highly variable, ranging from no symptoms to congestive heart failure, arrhythmias, and systemic thromboemboli. LVNC is genetically heterogeneous and can be inherited as an autosomal dominant or X-linked recessive disorder. It is also linked to mutations in several genes, encoding the sarcomeric proteins, such as myosin heavy chain 7 (MYH7). MYH7 encodes the β-myosin heavy chain, expressed in the cardiac muscle. The operative indication for patients with non-isolated LVNC is unclear. Here, we report the first successful case of surgical repair of a ventricular septal defect (VSD) in an infant with non-isolated LVNC associated with a novel MYH7 mutation. This mutation leads to the substitution of 7 amino acid residues (671-677) in the actin-binding region of the protein. After the VSD operation, the patient's congestive heart failure and pulmonary hypertension improved. His condition has remained stable for 18 months with pharmacotherapy comprising diuretics, an angiotensin converting enzyme inhibitor, and a β-blocker. Although the postsurgical observational period was short, the findings indicate that LVNC mutation analyses may facilitate surgical decisions and help predict clinical courses.

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Novel Gene Mutations in Patients With Left Ventricular Noncompaction or Barth Syndrome

Abstract: These data demonstrate genetic heterogeneity in LVNC, with mutation of a novel gene, alpha-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.

Cited by 507 publications

References 33 publications

Infantile Dilated X-Linked Cardiomyopathy, G4.5 Mutations, Altered Lipids, and Ultrastructural Malformations of Mitochondria in Heart, Liver, and Skeletal Muscle

Infantile Dilated X-Linked Cardiomyopathy, G4.5 Mutations, Altered Lipids, and Ultrastructural Malformations of Mitochondria in Heart, Liver, and Skeletal Muscle

The pathogenicity of genetic variants previously associated with left ventricular non‐compaction

Surgical Repair of Left Ventricular Noncompaction in a Patient with a Novel Mutation of the Myosin Heavy Chain 7 Gene

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