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G Bonne

Publications and source records attributed to G Bonne.

51 records · Page 3Linked to original sources
PubMed1997

Organization and sequence of human cardiac myosin binding protein C gene (MYBPC3) and identification of mutations predicted to produce truncated proteins in familial hypertrophic cardiomyopathy.

Cardiac myosin binding protein C (MyBP-C) is a sarcomeric protein belonging to the intracellular immunoglobulin superfamily. Its function is uncertain, but for a decade evidence has existed for both structural and regulatory roles. The gene encoding cardiac MyBP-C (MYBPC3) in humans is located on chromosome 11p11.2, and mutations have been identified in this gene in unrelated families with familial hypertrophic cardiomyopathy (FHC). Detailed characterization of the MYBPC3 gene is essential for studies on gene regulation, analysis of the role of MyBP-C in cardiac contraction through the use of recombinant DNA technology, and mutational analyses of FHC. The organization of human MYBPC3 and screening for mutations in a panel of French families with FHC were established using polymerase chain reaction, single-strand conformation polymorphism, and sequencing. The MYBPC3 gene comprises > 21,000 base pairs and contains 35 exons. Two exons are unusually small in size, 3 bp each. We found six new mutations associated with FHC in seven unrelated French families. Four of these mutations are predicted to produce truncated cardiac MyBP-C polypeptides. The two others should each produce two aberrant proteins, one truncated and one mutated. The present study provides the first organization and sequence for an MyBP-C gene. The mutations reported here and previously in MYBPC3 result in aberrant transcripts that are predicted to encode significantly truncated cardiac MyBP-C polypeptides. This spectrum of mutations differs from the ones previously observed in other disease genes causing FHC. Our data strengthen the functional importance of MyBP-C in the regulation of cardiac work and provide the basis for further studies.

Base Sequence↗
PubMed1997

Penetrance of familial hypertrophic cardiomyopathy.

Familial hypertrophic cardiomyopathy (FHC) is an autosomal dominant cardiac disease for which the penetrance remains a much-debated issue. Since the recent identification of the genes involved in the disease, the penetrance of FHC has not been reassessed in a large genotyped population. The aim of our study was therefore to evaluate it, according to age and sex, in ten families with previously identified mutations. Among 178 individuals we studied, 90 were genetically affected (9 different mutations in 3 genes). We found that penetrance, assessed by classical echocardiographic and electrocardiographic criteria, was (1) incomplete: 69%; (2) age-related: 55% between 10 and 29 years old, 75% between 30 and 49 y. and 95% over 50 y.; (3) greater in males than in females: 77% vs 58%, age-adjusted odds ratio: 3.98, CI 95%: 1.34 to 11,48; (4) similar for the genes analyzed. The consequences of these results for genetic counseling and linkage analyses are discussed.

Adolescent↗
PubMed1996

Codon 102 of the cardiac troponin T gene is a putative hot spot for mutations in familial hypertrophic cardiomyopathy.

BACKGROUND: Familial hypertrophic cardiomyopathy is a phenotypically and genetically heterogeneous disease. In some families, the disease is linked to the CMH2 locus on chromosome 1q3, in which the cardiac troponin T gene (TNNT2) has been identified as the disease gene. The mutations found in this gene appear to be associated with incomplete penetrance and poor prognosis. Because mutational hot spots offer unique possibilities for analysis of genotype-phenotype correlations, new missense mutations that could define such hot spots in TNNT2 were looked for in unrelated French families with familial hypertrophic cardiomyopathy. METHODS AND RESULTS: Family members were genotyped with microsatellite markers to detect linkage to the four known disease loci. In family 715, analyses showed linkage to CMH2 only. To accurately position potential mutations on TNNT2, its partial genomic organization was established. Screening for mutations was performed by single-strand conformation polymorphism analysis and sequencing. A new missense mutation, Arg102Leu, was identified in affected members of family 715 because of a G-->T transversion located in the 10th exon of the gene. Penetrance of this new mutation is complete; echocardiographic data show a wide range of hypertrophy; and there was no sudden cardiac death in this family. CONCLUSIONS: The codon 102 of the TNNT2 gene is a putative mutational hot spot in familial hypertrophic cardiomyopathy and is associated with phenotypic variability. Analysis of more pedigrees carrying mutations in this codon is necessary to better characterize the clinical and prognostic implications of TNNT2 mutations.

Adult↗
PubMed1995

Cardiac myosin binding protein-C gene splice acceptor site mutation is associated with familial hypertrophic cardiomyopathy.

Familial hypertrophic cardiomyopathy (FHC) is an autosomal dominant disease characterized by a ventricular hypertrophy predominantly affecting the interventricular septum and associated with a large extent of myocardial and myofibrillar disarray. It is the most common cause of sudden death in the young. In the four disease loci found, three genes have been identified which code for beta-myosin heavy chain, cardiac troponin T and alpha-tropomyosin. Recently the human cardiac myosin binding protein-C (MyBP-C) gene was mapped to chromosome 11p11.2 (ref. 8), making this gene a good candidate for the fourth locus, CMH4 (ref. 5). Indeed, MyBP-C is a substantial component of the myofibrils that interacts with several proteins of the thick filament of the sarcomere. In two unrelated French families linked to CMH4, we found a mutation in a splice acceptor site of the MyBP-C gene, which causes the skipping of the associated exon and could produce truncated cardiac MyBP-Cs. Mutations in the cardiac MyBP-C gene likely cause chromosome 11-linked hypertrophic cardiomyopathy, further supporting the hypothesis that hypertrophic cardiomyopathy results from mutations in genes encoding contractile proteins.

Amino Acid Sequence↗
PubMed1994

Expression of cytochrome c oxidase subunits encoded by mitochondrial or nuclear DNA in the muscle of patients with zidovudine myopathy.

The present study was carried out to determine whether a selective decrease of mitochondrial (mt) DNA-encoded cytochrome c oxidase (CCO) subunits occurs in zidovudine myopathy, as expected with a compound known to induce selective mtDNA depletion. Fourteen HIV-infected patients with zidovudine myopathy were studied. Thirteen had partial CCO deficiency assessed by histochemistry. Western blot analysis of CCO subunits (II/III, IV, Va, Vb, VIa, VIb, VIc, VIIa, VIIb, and VIIc) was performed on muscle biopsy samples. We evaluated the mtDNA-encoded subunits to nuclear DNA-encoded subunits ratio with the II/III to IV ratio. Patients had either a selective decrease of mtDNA-encoded CCO subunits (3 patients), or an overall decrease affecting both mtDNA-and nuclear DNA-encoded subunits (5 patients), or a normal expression of CCO subunits (6 patients). Positive correlations could not be established between the pattern of expression of CCO subunits and total zidovudine intake, degree of inflammation, and percentages of ragged-red fibers or CCO-deficient fibers. The finding of a decrease of both mtDNA- and nuclear DNA-encoded CCO subunits suggests that a factor additional to zidovudine could be implicated in the pathogenesis of the myopathy, at least in some patients. New insights into the pathogenesis of zidovudine myopathy might come from the use of more sensitive methods, including evaluation of CCO subunits in single fibers.

Adult↗
PubMed1993

Expression of human cytochrome c oxidase subunits during fetal development.

Expression of human cytochrome c oxidase (COX) subunits was examined at fetal (20-28 weeks) and adult state by Northern blot hybridization with mRNA from liver, heart, skeletal muscle, and intestine. The data were related to COX and citrate synthase activities and to immunodetected COX subunits (II/III, IV, VIIaH). In liver little changes of COX transcripts are observed from fetal to adult state. In contrast, in heart and skeletal muscle all transcripts of COX subunits increase between 2-20-fold, when related to the amount of 28S rRNA. In fetal heart and skeletal muscle the relative amounts of the liver-type transcripts of subunit VIa were 30% and 25% from total VIa transcripts (VIaL+VIaH), respectively, but decrease to only 2-5% at adult state. The liver-type transcripts of subunit VIIa occur to 50% in fetal heart and skeletal muscle, which remained unchanged in adult heart and decrease to 5-8% in adult skeletal muscle. The results clearly indicate a switch of gene expression in heart and skeletal muscle during development, from the liver type to the heart/muscle type of subunit VIa (and partly VIIa).

Adult↗
PubMed1993

Defect in the lipoyl-bearing protein X subunit of the pyruvate dehydrogenase complex in two patients with encephalomyelopathy.

Among the many metabolic encephalomyelopathies caused by deficiencies in the pyruvate dehydrogenase complex (PDHC), nearly all involve its E1 subunit. We describe two new familial cases of PDHC deficiency with encephalomyelopathy, chronic lactic acidemia, and a normal E1 subunit of PDHC but deficiency in another component. Activity of PDHC was measured in cultured skin fibroblasts and skeletal muscle, and immunoblot studies were performed on mitochondrial extracts from skin fibroblasts. Spectra of muscle tissue, obtained in vivo with phosphorus 31 nuclear magnetic resonance, were recorded both at rest and with exercise. The PDHC activity was markedly reduced to 10% to 20% of normal values in both cultured skin fibroblasts and skeletal muscle. Immunoblotting of skin fibroblast mitochondrial extracts showed a specific deficiency in the protein X component of PDHC but normal E1, E2, and E3 components. Spectra obtained with 31P nuclear magnetic resonance showed alterations compatible with those found in mitochondrial myopathies. This is the second description of an encephalomyelopathy associated with a specific absence of the lipoyl-containing protein X component, which has a structural role in the formation of a functional PDHC.

Child, Preschool↗
PubMed1993

E1 pyruvate dehydrogenase deficiency in a child with motor neuropathy.

We report the case of a boy who developed a motor neuropathy during infectious episodes at 18 mo and 3 y of age. When he was 7 y old, he suffered persistent weakness and areflexia; his resting lactate and pyruvate values were 3.65 mM and 398 microM, respectively (controls: 1.1 +/- 0.3 mM and 90 +/- 22 microM), and an exercise test demonstrated a lactic acidosis (13.6 mM; controls: 6.4 +/- 1.3 mM) with a high pyruvate level (537 microM; controls: 176 +/- 15 microM) and a low lactate/pyruvate ratio (24.2; controls: 35 +/- 2). The results of polarographic studies on muscle mitochondria suggested a defect in pyruvate oxidation (pyruvate 17 ng atom O/min/mg protein; controls: 115 +/- 42), whereas glutamate, palmitoylcarnitine, and succinate were good respiratory substrates. The activity of total pyruvate dehydrogenase complex (PDHC) in muscle mitochondria and in fresh mononuclear cells was markedly decreased (9.7 and 0.054 nmol 14CO2/min/mg protein, respectively; controls: 123 +/- 4.5 and 0.733 +/- 0.03, respectively). Immunochemical analysis in muscle mitochondria demonstrated an absence of the alpha and beta E1 PDHC subunits. After 2 y of treatment with 500 mg/d thiamine, the patient was clinically improved. A genetic study of the main regions of mutations (exon 10 and 11) in the X chromosome encoding for the E1 alpha subunit of PDHC did not show any mutation. These data indicate that, although genetically different, this case enters in a very rare category of patients with PDHC deficiency without cerebral dysfunction and improved by thiamine + L-carnitine therapy.

Base Sequence↗
PubMed1992

Kearns-Sayre syndrome with sideroblastic anemia: molecular investigations.

The progressive syndrome of Kearns-Sayre has been studied at the clinical, biochemical and genetic levels in a patient. Clinical arguments suggest an evolution from Pearson's disease to Kearns-Sayre syndrome. The respiratory chain activities were low, and Southern blot analysis, together with gene sequencing, showed a heteroplasmic deletion of 7767 base pairs in a significant proportion of the mitochondrial DNA in different tissues. Protein synthesis studies on lymphoblasts did not reveal any translation of the new reading frame created by the deletion, although the corresponding deleted mitochondrial DNA sequence is transcribed.

Anemia, Sideroblastic↗
PubMed1991

Zidovudine myopathy: a distinctive disorder associated with mitochondrial dysfunction.

Muscle biopsy specimens were obtained from 48 human immunodeficiency virus-infected patients suffering from various neuromuscular symptoms. Microscopic examination by conventional and electron microscopy revealed a characteristic structural myopathy associated with mitochondrial changes in 13 patients, all of whom had received long-term zidovudine therapy. The mean cumulative dose they had received (498 +/- 145 gm) was significantly higher than that of the other 14 zidovudine recipients of the study. They suffered from a progressive, usually painful, proximal myopathy with pronounced wasting, normal-to-moderately elevated creatine kinase levels, and a myopathic electromyographic pattern. The condition usually improved after withdrawal of the drug. Assay of mitochondrial enzymes, including succinate-cytochrome c reductase, cytochrome c oxidase, and citrate synthase, showed a decline in respiratory chain capacity. Southern blot analysis of mitochondrial DNA showed no abnormality. It is likely that mitochondrial dysfunction, probably resulting from drug-induced inhibition of the mitochondrial DNA polymerase, is implicated in the pathogenesis of this complication of zidovudine therapy.

Adult↗
PubMed1991

Genetic biochemical and pathophysiological characterization of a familial mitochondrial encephalomyopathy (MERRF).

Myoclonic epilepsy with ragged-red fibers (MERRF) syndrome is a neuromuscular disorder characterized by mitochondrial myopathy and progressive myoclonus epilepsy. A heteroplasmic A to G transition mutation in the mitochondrial encoded tRNA(Lys) gene at nucleotide pair 8344 has been suggested to be linked to the MERRF-syndrome. We have investigated biochemically and histochemically muscle biopsies and studied the mitochondrial genomes of hair, blood and muscle tissue of a family including three cases of MERRF-syndrome as well as unaffected relatives within the maternal lineage. Sequence analysis of the mtDNAs, performed after amplification by the polymerase chain reaction (PCR), confirmed the A to G transition mutation in the tRNA(Lys) gene at position 8344. The additional point mutation at nucleotide pair 750 in the 12 S rRNA gene, which was also found by Shoffner et al. (1990), however, was absent in all investigated tissues. Quantitative analysis of the percentage of mutated mtDNA by mispairing PCR (Seibel et al., 1990) revealed variable contents in different tissues and individuals, including unaffected family members. Mitochondrial protein synthesis in cultured fibroblasts from MERRF patients revealed diminished incorporation of 35S-methionine into lysine-containing peptides.

Adolescent↗
PubMed1991

[Mitochondrial function and mitochondrial DNA in a series of 64 patients suspected of having mitochondrial myopathy].

Biochemical results concerning 64 patients suspected of mitochondrial myopathies are presented. Four clinical groups were studied including 21 encephalomyopathies, 42 ocular myopathies, 8 isolated myopathies and 3 cardiomyopathies. In 26 cases, the coexistence of a normal mitochondrial DNA and a mutated mitochondrial DNA (heteroplasmy) was found (19 simple deletions, 4 multiple deletions and 3 punctual mutations) and all cases presented with ocular disorders (excepted 2 cases with MERRF). Furthermore, 1 complex I deficiency (1 ocular myopathy), 1 complex IV deficiency (1 adult encephalomyopathy type Leigh), 3 complexes I + IV deficiencies (2 cases with a cardiomyopathy and 1 familial MELAS) and 2 pyruvate (1 adult from of Leigh's encephalomyopathy) dehydrogenase deficiencies (clinically and genetically different) did not show evidence of mitochondrial DNA mutation.

Blotting, Western↗
PubMed1986

Serum bone GLA-protein in growth hormone deficient children.

Serum bone GLA-protein (BGP), a sensitive and specific marker of bone formation, was measured in 54 normal children and in 50 children with growth disorders. In normal children, the pattern of variations of serum BGP with age was similar to the pattern of variations of the growth velocity. Mean serum BGP was very high during the first year of life (25.3 +/- 8.5 ng/ml), decreased to 14.8 +/- 2.2 ng/ml from 2 to 6 years, increased to 18.4 +/- 4.1 ng/ml from 7 to 10 years and to 18.8 +/- 6.5 ng/ml from 11 to 14 years. After puberty, mean sBGP decreased to 12.9 +/- 5.4 ng/ml from 15 to 18 years and to 6.5 +/- 1.4 ng/ml in young adults. In 32 patients with untreated growth hormone (GH) deficiency, mean sBGP was markedly lower than in age matched controls (6.8 +/- 4.4 ng/ml vs. 17.5 +/- 4.9 ng/ml, p less than .001). In 19 patients with GH deficiency who were undergoing treatment with human GH, sBGP was higher than in untreated patients (20.5 +/- 9.3 ng/ml vs. 6.8 +/- 4.4 ng/ml, p less than .001) and was not different from controls. Repeated measurements performed in 14 GH-deficient patients under chronic GH therapy showed that serum BGP: (1) increased in most patients during treatment (p less than .005); (2) was correlated with the duration of treatment (p less than .001); (3) decreased to pretreatment values after discontinuing therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMedDate not supplied

[The laminopathy saga].

AIMS: Our aim was to clinically characterise Emery-Dreifuss muscular dystrophy, to differentiate the X-linked forms of inheritance from the forms involving autosomal dominant inheritance, from a genetic point of view, and to describe the phenotypical heterogeneity of mutations in the LMNA gene itself. DEVELOPMENT: We describe the identification of the mutations in the lamina A/C gene, the LMNA gene, which was made possible thanks to the networks allowing workers in different countries to collaborate. Mutations in this gene are responsible for autosomal dominant Emery-Dreifuss disease, as well as other diseases that are phenotypically very distinct, such as limb girdle muscular dystrophy associated with cardiac conduction defects (LGMD1B), dilated myocardiopathy with conduction defects (DCM-CD), Dunnigan-type familial partial lipodystrophy (FPLD) and, finally, an autosomal recessive form of axonal neuropathy or Charcot-Marie-Tooth disease type 2 (AR-CMT). CONCLUSIONS: Laminas are intermediate filaments that constitute the inner nuclear membrane of any cell and the mutations in the lamina A/C gene can give rise to such distinct clinical patterns as a kind of muscular dystrophy that is similar to the well known X-linked Emery-Dreifuss disease or a form of Charcot-Marie-Tooth-type neuropathy. Work is currently being conducted on an experimental animal model capable of providing us with a better understanding of the physiopathological mechanisms involved in the production of these tissue-specific diseases, although they are due to mutations in a gene that codifies for proteins that are expressed all over.

Animals↗