RESUMO
Seven out of eight piglets which were susceptible to malignant hyperthermia (MHS) died when subjected to a heat challenge which was well tolerated by controls. The piglets which succumbed developed the classical clinical and biochemical changes of malignant hyperthermia before they died. These results show that overheating alone can trigger malignant hyperthermia in susceptible animals. Because the biochemical basis of malignant hyperthermia is similar in both humans and pigs, these observations suggest that overheating can also trigger malignant hyperthermia in humans. The susceptibility to overheating in malignant hyperthermia susceptible humans and animals probably explains why the myopathy which predisposes to this condition has also been reported to predispose to heat-stroke and the sudden infant death syndrome. In view of this, particular care to prevent overheating should be taken in infants of parents who are susceptible to malignant hyperthermia.
Assuntos
Temperatura Alta/efeitos adversos , Hipertermia Maligna/etiologia , Animais , Gasometria , Feminino , Humanos , Lactente , Masculino , Hipertermia Maligna/sangue , Fatores de Risco , Morte Súbita do Lactente/etiologia , SuínosRESUMO
The molecular defect predisposing to the majority of malignant hyperthermia (MH) cases is unknown, although various point mutations in the ryanodine receptor gene (RYR1) have been associated with susceptibility in a small proportion of cases. We report here that one of these, the Arg163Cys substitution, does not cosegregate with MH susceptibility. Comparison of cDNA sequences encoding the skeletal muscle specific components of the dihydropyridine receptor alpha 1 subunit between MH susceptible (MHS) and MH non-susceptible (MHN) patients was made in subjects without the reported MH linked RYR1 mutations. There were no differences within the sequence encoding the II-III loop or the IS3/IS3-IS4 segment, excluding defects in these functional segments of the alpha 1 subunit as frequent causes of MH.
Assuntos
Canais de Cálcio/genética , Hipertermia Maligna/genética , Proteínas Musculares/genética , Mutação Puntual , Sequência de Bases , Cálcio/metabolismo , Canais de Cálcio/química , Canais de Cálcio Tipo L , DNA Complementar/genética , Feminino , Heterogeneidade Genética , Predisposição Genética para Doença , Humanos , Masculino , Dados de Sequência Molecular , Linhagem , Canal de Liberação de Cálcio do Receptor de Rianodina , Retículo Sarcoplasmático/metabolismoRESUMO
We have cloned and sequenced the cDNA encoding triadin, a junctional terminal cisternae protein from human skeletal muscle. The cDNA, 2941 base pairs in length, encodes a protein of 729 amino acids with a predicted molecular mass of 81,545 Da. Hydropathy analysis indicates that triadin of human skeletal muscle has the same topology in the myoplasmic, transmembrane and sarcoplasmic reticulum luminal domains as that of triadin from rabbit skeletal muscle. The number and relative position of potential modulation sites are also conserved between the human and rabbit proteins. The cDNA sequence of the predicted sarcoplasmic reticulum luminal domain of human triadin diverged from that of rabbit, with an observed similarity of 82%, translating to an identity of 77% in amino acid sequence. Two insertions of 9 and 12 residues in the amino acid sequence were observed in the predicted luminal domain of triadin, although the structural and functional consequences of such insertions are expected to be minimal. Using fluorescence in situ hybridisation, we have assigned the gene encoding human triadin to the long arm of chromosome 6 in the region 6q22-6q23. Our structural analysis of human triadin supports a central role for this protein in the mechanism of skeletal muscle excitation/contraction coupling.
Assuntos
Proteínas de Transporte , Cromossomos Humanos Par 6/genética , DNA Complementar/genética , Proteínas Musculares/genética , Músculo Esquelético/metabolismo , Sequência de Aminoácidos , Animais , Sequência de Bases , Mapeamento Cromossômico , Clonagem Molecular , Primers do DNA/genética , Expressão Gênica , Humanos , Hibridização in Situ Fluorescente , Dados de Sequência Molecular , Peso Molecular , Proteínas Musculares/química , Reação em Cadeia da Polimerase , Coelhos , Homologia de Sequência de Aminoácidos , Especificidade da EspécieRESUMO
Treatment of anti-ovalbumin rabbit IgG with diethylpyrocarbonate (DEPC) at concentrations up to 100 microM led to a progressive decrease in the rates of formation of insoluble immune complexes, without affecting the final extent of immune complex formation. DEPC concentrations approximately 10-fold higher were needed to give comparable decreases in the rates of immune complex formation by F(ab')2. Treatment of DEPC-treated IgG with hydroxylamine led to substantial restoration of the rates of formation of insoluble immune complexes. Carbethoxylation of two histidine residues per IgG molecule had little effect on rates of formation of insoluble immune complexes, but these rates were markedly decreased in samples of IgG with four to five histidines per molecule modified. There were parallel decreases in the protein A-binding activity and in the rates of formation of insoluble immune complexes in IgG treated with increasing concentrations of DEPC. The presence of complement protein C1q restored the rates of formation of insoluble immune complexes of DEPC-treated IgG.
