Peutz-Jeghers syndrome (PJS) is a dominantly inherited human disorder characterized by gastrointestinal hamartomatous polyposis and mucocutaneous melanin pigmentation. LKB1 (STK11) serine͞threonine kinase is the product of the causative gene of PJS, which has been mapped to chromosome 19p13.3. However, several studies have produced results that are not consistent with a link between LKB1 gene mutation and PJS. We constructed a knockout gene mutation of Lkb1 to determine whether it is the causative gene of PJS and to examine the biological role of the Lkb1 gene. Lkb1 ؊/؊ mice died in utero between 8.5 and 9.5 days postcoitum. At 9.0 days postcoitum, Lkb1 ؊/؊ embryos were generally smaller than their age-matched littermates, showed developmental retardation, and did not undergo embryonic turning. Multiple gastric adenomatous polyps were observed in 10-to 14-month-old Lkb1 ؉/؊ mice. Our results indicate that functional Lkb1 is required for normal embryogenesis and that it is related to tumor development. The Lkb1 ؉/؊ mouse is suitable for studying molecular mechanism underlying the development of inherited gastric tumors in PJS.tumor ͉ embryo development

To provide insight into the polycyclization mechanism of squalene by squalene-hopene cyclase (SHC) from Alicyclobacilus acidocaldarius, some analogs of nor- and bisnorsqualenes were synthesized including the deuterium-labeled squalenes and incubated with the wild-type SHC, leading to the following inferences. (1) The deprotonation reaction for the introduction of the double bond of the hopene skeleton occurs exclusively from the Z-methyl group on the terminal double bond of squalene. (2) 3R-Oxidosqualene was folded in a boat conformation for the A-ring construction, while the 3S-form was in a chair structure. (3) The terminal two methyl groups are indispensable both for the formation of the 5-membered E-ring of the hopene skeleton and for the initiation of the polycyclization cascade, but the terminal Z-methyl group has a more crucial role for the construction of the 5-membered E-ring than the E-methyl group. (4) Some of the novel terpene skeletons, 36, 37, 39 and 40, were created from the analogs employed in this investigation.

We present a reliable, rapid, and economical multiplex amplified product-length polymorphism (APLP) method for analyzing the haplogroup-diagnostic mitochondrial single-nucleotide polymorphisms (mtSNPs) in East Asian populations. By examining only 36 haplogroup-specific mtSNPs in the coding region by using four 9-multiplex polymerase chain reaction (PCR) and subsequent electrophoresis, we could safely assign 1815 individuals from 8 populations of Japanese, Korean, Chinese, and Germans to 45 relevant haplogroups. This multiplex APLP analysis of coding-region mtSNPs for haplogrouping is especially useful not only for molecular phylogenetic studies but also for large-scale association studies due to its rapid and economical nature. This is the first panel of mtSNPs in the coding region to be used for haplogrouping of East Asian populations.

SummaryThe membrane-associated transporter protein (MATP) plays an important role in melanin synthesis. The L374F mutation in the SLC45A2 gene encoding MATP has been suggested to be associated with skin colour in major human populations. In this study more detailed distribution of the F374 allele was investigated in 1649 unrelated subjects from 13 Eurasian populations and one African population. The highest allele frequency was observed in Germans (0.965); French and Italians showed somewhat lower frequencies; and Turks had an intermediate value (0.615). Indians and Bangladeshis from South Asia were characterized by low frequencies (0.147 and 0.059, respectively). We also found the F374 allele in some East and Southeast Asian populations, and explained this by admixture. Haplotype analysis revealed that the haplotype diversity was much lower in Germans than in Japanese, and suggest that the L374F mutation occurred only once in the ancestry of Caucasians. The large differences in distribution of the F374 allele and its haplotypes suggest that this allele may be an important factor in hypopigmentation in Caucasian populations.

In this study, we evaluated the relationship between the endothelium-dependent vasodilation and salt sensitivity in patients with essential hypertension. Fifteen untreated hypertensive male patients (age, 29 to 54 years) were sodium restricted (5 g/day) for 1 week, and placed on a high salt diet (20 g/day) the second week. At the end of each period, measurements of forearm vascular responses to drugs (acetylcholine, 3 to 24 microg/min; sodium nitroprusside, 0.15 to 1.2 microg/min; norepinephrine, 0.15 to 1.2 microg/min; and N(G)-monomethyl-L-arginine [L-NMMA], 1 to 8 micromol/min) were obtained by using strain-gauge venous plethysmography. Subjects were divided into two groups according to the blood pressure response to sodium loading: salt-sensitive hypertensive group (24-h mean increase of arterial pressure > or = 10%; n = 6) and salt-resistant group (< 10%; n = 9). The two groups showed no significant difference in clinical data or mean arterial pressure during low salt intake. The dose-dependent vasodilation induced by acetylcholine was significantly reduced (P < .05) in the salt-sensitive hypertensive patients v the salt-resistant patients regardless of sodium loading. There were no differences between the two groups in response to sodium nitroprusside, norepinephrine, or L-NMMA. These results indicate that vasodilation to acetylcholine is reduced in salt-sensitive hypertensive patients even on restricted sodium diets. This may contribute to blood pressure elevation when sodium intake is increased.