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T V McCarthy

Publications and source records attributed to T V McCarthy.

46 records · Page 3Linked to original sources
PubMed1990

Localization of the malignant hyperthermia susceptibility locus to human chromosome 19q12-13.2.

Malignant hyperthermia (MH) is an inherited human skeletal muscle disorder and is one of the main causes of death due to anaesthesia. The reported incidence of MH varies from 1 in 12,000 in children to 1 in 40,000 in adults. MH is triggered in susceptible people by all commonly used inhalational anaesthetics; it is characterized by a profoundly accelerated muscle metabolism, contractures, hyperthermia and tachycardia. Susceptibility to MH (MHS) is predicted by contracture tests on muscle tissue obtained by biopsy. An almost identical disorder known as porcine MH exists in pigs. The genetics of the porcine syndrome have been extensively studied; the locus controlling expression of porcine MH is genetically linked to the glucose phosphate isomerase locus (GPI). In man, GPI has been mapped to the q12-13.2 region of chromosome 19 (refs 10-12). We have now investigated genetic linkage in several extended Irish pedigrees in which MHS is segregating as an autosomal dominant trait. Here we show linkage between MHS and DNA markers from the GPI region of human chromosome 19 with a maximum log likelihood ratio (lod score) of 5.65 at the CYP2A locus. These results indicate that human and porcine MH are most probably due to mutations in homologous genes, and also provide a potentially accurate and noninvasive method of diagnosis for MHS.

Animals↗
PubMed1990

Recent developments in the molecular genetics of malignant hyperthermia: implications for future diagnosis at the DNA level.

Molecular genetic linkage studies on the inherited human disorder malignant hyperthermia have resulted in the mapping of the locus for malignant hyperthermia susceptibility (MHS) to the twenty centimorgan genetic interval in the q12-13.2 region of chromosome 19 defined by the anonymous polymorphic DNA markers D19S9 and BCL3. The mapping of the MHS locus to this interval now allows diagnosis of MHS in selected families with an accuracy of 97.5% using closely linked polymorphic DNA markers.

Chromosomes, Human, Pair 19↗
PubMed1990

Current views of the molecular basis of the malignant hyperthermia syndrome.

The muscle disease malignant hyperthermia is a disorder of intracellular free Ca2+ regulation in both humans and pigs. Current evidence indicates that the Ca2+ channel of the sarcoplasmic reticulum of MH muscle is abnormally sensitive to Ca2+ and to halothane. Mitochondria, the sarcolemma and the transverse tubule appear not to be involved in primary pathogenesis of MH. Molecular genetic studies indicate that the MH gene is on human chromosome 19 and that the likely candidate gene is that coding for the Ca2+ channel.

Calcium↗
PubMed1986

The intracellular signal for induction of resistance to alkylating agents in E. coli.

The E. coli ada gene positively controls its own expression and that of other genes (alkA, alkB, aidB) involved in repair of DNA alkylation damage. The cloned ada and alkA genes and purified Ada protein have been used in cell-free systems to identify the inducing signal. Self-methylation of the Ada protein by transfer of a methyl group from a phosphotriester in alkylated DNA to a cysteine residue in the protein converts it to an activator of transcription. The covalently modified Ada protein binds specifically to promoter regions containing the sequence d(AAANNAAAGCGCA) immediately upstream of the RNA polymerase binding sites. This is apparently the first example of conversion of a regulatory gene product to a transcriptional activator by a posttranslational modification event.

Alkylating Agents↗
PubMed1985

Methyl phosphotriesters in alkylated DNA are repaired by the Ada regulatory protein of E. coli.

The E. coli ada+ gene product that controls the adaptive response to alkylating agents has been purified to apparent homogeneity using an overproducing expression vector system. This 39 kDa protein repairs 0(6)-methylguanine and 0(4)-methylthymine residues in alkylated DNA by transfer of the methyl group from the base to a cysteine residue in the protein itself. The Ada protein also corrects one of the stereoisomers of methyl phosphotriesters in DNA by the same mechanism, while the other isomer is left unrepaired. Different cysteine residues in the Ada protein are used as acceptors in the repair of methyl groups derived from phosphotriesters and base residues.

Alkylation↗
PubMed1984

Inducible repair of O-alkylated DNA pyrimidines in Escherichia coli.

The three miscoding alkylated pyrimidines O2-methylcytosine, O2-methylthymine and O4-methylthymine are specifically recognized by Escherichia coli DNA repair enzymes. The activities are induced as part of the adaptive response to alkylating agents. O2-Methylcytosine and O2-methylthymine are removed by a DNA glycosylase, the alkA+ gene product, which also acts on N3-methylated purines. O4-Methylthymine is repaired by a methyltransferase, previously known to correct O6-methylguanine by transfer of the methyl group to one of its own cysteine residues. It is proposed that certain common structural features of the various methylated bases allow each of the two inducible repair enzymes to recognize and remove several different kinds of lesions from alkylated DNA.

Alkylating Agents↗