The spitz gene encoding a TGF-~ homolog, has been shown to affect a subset of developmental processes that are similar to those regulated by DER, the Drosophila EGF receptor homolog. This work demonstrates that

Familial hyperkalemia and hypertension (FHH; pseudohypoaldosteronism type II) is an autosomal dominant disorder characterized by hyperkalemia, hypertension, and low renin. WNK1 kinase overexpression and WNK4 kinase inactivating missense mutations cause FHH. When expressed in frog oocyte, WNK4 inhibits Na-Cl cotransporter surface expression, and WNK1 relieves this inhibition. We have reported hypercalciuria in subjects with the WNK4 Q565E mutation. In contrast, in subjects with WNK1 overexpression, normocalciuria was found. Here we report a major extension of our previously described kindred that contains 34 subjects, 18 of them affected by the mutation. Hypertension was diagnosed in 13 affected subjects at the age of 31 +/- 12 yr. Five of the affected or obligatory affected subjects had stroke, in four at the age of 50-62 yr. Seven subjects with FHH were diagnosed 27 yr previously. All four subjects who were normotensive at diagnosis became hypertensive during follow-up. The mean time between detection of hyperkalemia and appearance of hypertension was 13 yr. In the extended kindred, compared with the unaffected subjects, affected subjects had hyperkalemia, low transtubular potassium gradient, hyperchloremia, low bicarbonate, higher aldosterone, and marked suppression of renin. Urinary calcium levels in affected and unaffected subjects were 0.85 +/- 0.27 and 0.28 +/- 0.12 mmol/mmol creatinine, respectively (P < 0.0001). Hypercalciuria was accompanied by lower serum calcium levels [9.44 +/- 0.15 vs. 9.81 +/- 0.31 mg/dl (2.36 +/- 0.04 vs. 2.45 +/- 0.08 mmol/liter); P = 0.01], supporting a mechanism of renal calcium leak. The six affected, currently normotensive subjects had the same degree of hyperkalemia, hypercalciuria, and low renin as the affected hypertensive subjects. We conclude that in FHH with WNK4 mutations, with time all affected subjects will apparently develop hypertension. Hypercalciuria accompanies hyperkalemia, and both precede hypertension. Based on the recent findings that WNK4 regulates the renal outer medullary potassium channel as well as epithelial Cl(-)/base exchanger and the Na(+)-K(+)-2Cl(-) cotransporter, we suggest that WNK4 interacts with a calcium channel or transporter.

We suggest that Gsalpha is imprinted in the brain.

We have studied the effects of four nonnucleoside inhibitors, including the novel natural product inhibitor calanolide A, on molecular chimeras containing complementary segments of human immunodeficiency virus type 1 (HIV-1) and type 2 (HIV-2) reverse transcriptases (RTs). All four compounds specifically inhibited the DNA polymerase activity of HIV-1 RT but had no apparent effect on the RNase H activity of this enzyme or on the DNA polymerase or RNase H activity of HIW-2 RT. Three of these compounds showed the generally expected patterns of resistance and susceptibility with the various chimeric RTs. However, the inhibition patterns of the chimeric RTs by calanolide A provided evidence that there is a segment between residues 94 and 157 in HIV-1 RT that is critical for inhibition. However, the data also suggest that there may be a second segment located between amino acids 225 and 427 in HIV-1 RT that is also important for specifying susceptibility to the drug.Human immunodeficiency virus type 1 (HIV-1) and type 2 (HIV-2) are etiological agents responsible for AIDS (la, 33). As is true for all retroviruses, the virus-coded enzyme reverse transcriptase (RT) is a key enzyme in the early steps of the viral life cycle, since RT is required for the synthesis of unintegrated viral DNA from the viral RNA template (40,42,43). Reverse transcription, which does not appear to be required for normal cellular processes, is an attractive target for the development of potent anti-HIV drugs (12,30).Considering the complex nature of RT and the enzymatic reactions that RT catalyzes, it is not surprising that numerous compounds that inhibit the reverse transcription process have been found. However, most of these inhibitors can be grouped into two distinct classes (12, 30). The first class consists of nucleoside analogs, such as 3'-azido-2',3'-dideoxythymidine (AZT) and 2',3'-dideoxyinosine (ddl). These compounds, when incorporated into viral DNA by RT, cause premature chain termination of the nascent DNA strands. However, long-term therapy of HIV-infected patients has been limited by the toxicity of these agents and by the emergence of drug-resistant viral strains (12,15,24,25,30,39).A second class of inhibitors consists of complex aromatic compounds (11,12,14,16,17,23,29,32) (2,41). These compounds include derivatives of diarylsulfone (27), thiazolobenzimidazole (5-7), and sulfoxamine (unpublished data). Despite their chemical diversity, all of these compounds appear to belong to a common pharmacological class with functional similarity. HIV-1 RT mutants that arose following exposure to individual compounds in this class or that were generated by in vitro site-directed mutagenesis are crossresistant to the diverse members of this class. For example, mutants that are resistant to TIBO show cross-resistance to nevirapine and to pyridinone compounds (10,13,17,28,31,34,38). It was recently shown that nevirapine binds to a hydrophobic pocket in HIV-1 RT near, but distinct from, the active site of DNA polymerase (22). It seems likely ...