Familial hypomagnesemia with secondary hypocalcemia (OMIM 602014) is an autosomal recessive disease that results in electrolyte abnormalities shortly after birth. Affected individuals show severe hypomagnesemia and hypocalcemia, which lead to seizures and tetany. The disorder has been thought to be caused by a defect in the intestinal absorption of magnesium, rather than by abnormal renal loss of magnesium. Restoring the concentrations of serum magnesium to normal values by high-dose magnesium supplementation can overcome the apparent defect in magnesium absorption and in serum concentrations of calcium. Life-long magnesium supplementation is required to overcome the defect in magnesium handling by these individuals. We previously mapped the gene locus to chromosome 9q in three large inbred kindreds from Israel. Here we report that mutation of TRPM6 causes hypomagnesemia with secondary hypocalcemia and show that individuals carrying mutations in this gene have abnormal renal magnesium excretion.

The mechanism of hybrid-arrested translation by antisense oligodeoxynucleotides has been investigated with the rabbit reticulocyte lysate system. The oligonucleotides studied were directed against different regions of mouse a-or f-globin mRNAs. Freshly prepared reticulocyte lysates were found to contain 1-2% of the level of RNase H in nucleated cells. This level of activity was sufficient to cleave nearly 100% of the targeted mRNA at the site of hybridization with a complementary oligodeoxynucleotide in 1 hr under conditions of active translation. Using poly(rA)'oligo(dT) as a competitive inhibitor of the enzyme, hybrid arrest by oligodeoxynucleotides complementary to the sequence spanning the initiation codon or to a sequence in the coding region was found to be due entirely to cleavage of mRNA by RNase H. Hybridization of oligodeoxynucleotides adjacent to the cap site of 3globin mRNA, but not the a-globin mRNA, also inhibited protein synthesis directly. Even in this case, however, cleavage of the mRNA by RNase H was the predominant pathway of inhibition.

An F 2 population (n = 151) derived from Dahl salt-sensitive (S) and Lewis rats was raised on a 8% NaCl diet for 9 weeks and analyzed for blood pressure quantitative trait loci (QTL) by use of a whole genome scan. Chromosomes 5 and 10 yielded lod scores for linkage to blood pressure that were significant; chromosomes 1, 2, 3, 8, 16, 17, and 18 gave lod scores suggestive for linkage. Chromosome 7 gave a significant signal for heart weight with a lesser effect on blood pressure. Congenic strains were constructed by introgressing Lewis low-blood-pressure QTL alleles for chromosomes 1, 5, 10, and 17 into the S genetic background. Congenic strains for chromosomes 1, 5, and 10 had significantly lower blood pressure than S, proving the existence of QTL on these chromosomes, but the chromosome 17 congenic strain failed to trap a contrasting QTL allele. The QTL allele increasing blood pressure originated from S rats for all QTL except those on chromosomes 2 and 7 in which the Lewis allele increased blood pressure. Interactions between each QTL and every other locus in the genome scan yielded significant interactions between chromosomes 10 and 4, and between chromosomes 2 and 3.More than 30 years ago, Dahl et al. (1963) selectively bred rats for sensitivity (S rats) and resistance (R rats) to the hypertensive effect of a high-salt (NaCl) diet. Inbred strains of S and R rats were subsequently developed from Dahl's selectively bred lines (Rapp and Dene 1985). These strains are the prototypic animal model for studying salt-induced hypertension.S rats develop hypertension even on a low-salt diet, but this is markedly exacerbated by increased salt intake (Dahl et al. 1963;Rapp and Dene 1985). Chromosomal regions containing blood pressure quantitative trait loci (QTL) have been detected by the candidate gene approach starting in 1972 with a biochemical genetic marker for steroid 11␤-hydroxylase Dahl 1972a, 1976), and then in 1989 when restriction fragment-length polymorphisms first became available (Rapp et al. 1989). More recently, additional chromosomal regions containing blood pressure QTL were identified around candidate genes by use of Dahl rats and more modern genetic markers

Acid-sensing ion channels (ASICs) respond to acidosis that normally occurs after inflammation. We examined the expression of ASIC1, ASIC2, and ASIC3 mRNAs in lumbar DRG neurons before and 24h after carrageenan-induced muscle inflammation. Muscle inflammation causes bilateral increases of ASIC2 and ASIC3, but not ASIC1 (neither ASIC1a nor ASIC1b) mRNA, suggesting differential regulation of ASIC1 versus ASIC2 and ASIC3 mRNA. Similar mRNA increases were observed following inflammation in knockout mice: ASIC2 mRNA increases in ASIC3−/− mice; ASIC2 and ASIC3 mRNAs increase in ASIC1−/− mice. Prior behavioral studies in ASIC3−/− mice showed deficits in secondary hyperalgesia (increased response to noxious stimuli outside the site of injury), but not primary hyperalgesia (increased response to noxious stimuli at the site of injury). In this study, we show that ASIC1−/− mice surprisingly do not develop primary muscle hyperalgesia, but develop secondary paw hyperalgesia. In contrast and as expected, ASIC3−/− mice develop primary muscle hyperalgesia, but do not develop secondary paw hyperalgesia. The pharmacological utility of the non-selective ASIC inhibitor A-317567, given locally, was tested. A-317567 reverses both primary and the secondary hyperalgesia induced by carrageenan muscle inflammation. Thus, peripherally located ASIC1 and ASIC3 play different roles in the development of hyperalgesia after muscle inflammation.