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The X-linked gene G4.5 is responsible for different infantile dilated cardiomyopathies
P D'Adamo1, L Fassone, A Gedeon
1Institute of Genetics, Biochemistry and Evolution-CNR, Pavia, Italy.
Insights
Barth syndrome (BTHS) is an X-linked disorder caused by mutations in the G4.5 gene. This gene is also responsible for X-linked endocardial fibroelastosis and severe X-linked cardiomyopathy, linking these conditions molecularly.
Area of Science:
- Genetics
- Molecular Biology
- Cardiology
Background:
- Barth syndrome (BTHS) is an X-linked disorder with variable clinical features including cardiac and skeletal myopathy, short stature, and neutropenia.
- Cardiac failure due to dilatation and hypertrophy is a constant finding and the primary cause of early mortality in BTHS.
- X-linked cardiomyopathies with similar clinical manifestations have been reported, suggesting potential allelic relationships.
Purpose of the Study:
- To investigate the genetic basis of Barth syndrome and related X-linked cardiomyopathies.
- To analyze mutations in the G4.5 gene in patients with suspected BTHS and X-linked dilated cardiomyopathies.
- To establish the molecular link between BTHS, X-linked endocardial fibroelastosis, and severe X-linked cardiomyopathy.
Main Methods:
- Sequence analysis of the G4.5 gene in 11 familial cases (8 suspected BTHS, 3 X-linked dilated cardiomyopathies).
- Identification and characterization of mutations within the G4.5 gene.
- Correlation of genotype with clinical phenotype.
Main Results:
- Mutations in the G4.5 gene were identified in nine of the analyzed patients.
- Molecular studies confirmed that the G4.5 gene is responsible for BTHS, X-linked endocardial fibroelastosis, and severe X-linked cardiomyopathy.
- Severe phenotypes were associated with null mutations, while alternative or missense mutations correlated with less severe phenotypes.
Conclusions:
- The G4.5 gene is the causative gene for Barth syndrome, X-linked endocardial fibroelastosis, and severe X-linked cardiomyopathy.
- Genetic mutations in G4.5 explain the molecular basis for these previously distinct X-linked cardiac and myopathic disorders.
- The type of mutation in G4.5 (null vs. alternative/missense) influences the severity of the clinical phenotype.
Abstract:
Barth syndrome (BTHS) is an X-linked disorder characterized clinically by the associated features of cardiac and skeletal myopathy, short stature, and neutropenia. The clinical manifestations of the disease are, in general, quite variable, but cardiac failure as a consequence of cardiac dilatation and hypertrophy is a constant finding and is the most common cause of death in the first months of life. X-linked cardiomyopathies with clinical manifestations similar to BTHS have been reported, and it has been proposed that they may be allelic. We have recently identified the gene responsible for BTHS, in one of the Xq28 genes, G4.5. In this paper we report the sequence analysis of 11 additional familial cases: 8 were diagnosed as possibly affected with BTHS, and 3 were affected with X-linked dilated cardiomyopathies. Mutations in the G4.5 gene were found in nine of the patients analyzed. The molecular studies have linked together what were formerly considered different conditions and have shown that the G4.5 gene is responsible for BTHS (OMIM 302060), X-linked endocardial fibroelastosis (OMIM 305300), and severe X-linked cardiomyopathy (OMIM 300069). Our results also suggest that very severe phenotypes may be associated with null mutations in the gene, whereas mutations in alternative portions or missense mutations may give a "less severe" phenotype.