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We have recently shown that mutations in the gene encoding the transcription factor hepatocyte nuclear factor (HNF)-1alpha are the cause of one form of maturity-onset diabetes of the young (MODY3). Here, we report the exon-intron organization and partial sequence of the human HNF-1alpha gene. In addition, we have screened the ten exons and flanking introns of this gene for mutations in a group of 25 unrelated white subjects from Germany who presented with NIDDM before 35 years of age and had a first-degree relative with NIDDM. Mutations were identified in nine of these individuals, suggesting that mutations in the HNF-1alpha gene are a common cause of diabetes in German subjects with early-onset NIDDM and a family history of diabetes. Thus, screening for mutations in this gene may be indicated in subjects with early-onset NIDDM. Interestingly, three of the nine mutations occurred at the same site in exon 4 with insertion of a C in a polyC tract, centered around codon 290 (designated Pro291fsinsC), thereby resulting in a frameshift during translation and premature termination. Analyses of linked DNA polymorphisms in the HNF-1alpha gene indicated that the Pro291fsinsC mutation was present on a different haplotype in each subject, implying that the polyC tract represents a mutational hot spot. We have also identified the mutation in the HNF-1alpha gene in the Jutland pedigree, one of the original MODY pedigrees reported in the literature, as being a T-->G substitution in codon 241, resulting in the replacement of a conserved Cys by Gly (C241G). The information on the sequence of the HNF-1alpha gene and its promoter region will facilitate the search for mutations in other subjects and studies of the role of the gene in determining normal beta-cell functions.

Letter to the editors Maturity-onset diabetes of the young (MODY) at least ten times more common in Europe than previously assumed?

INTRODUCTION5-Hydroxytryptamine-3 (5-HT 3 ) receptor antagonists have been found to be potent anti-emetic drugs for chemotherapy-or radiation-induced nausea and vomiting.1±4 So far, four selective 5-HT 3 receptor antagonists (ondansetron, formerly GR 38032F; tropisetron, formerly ICS 205-930; granisetron, formerly BRL 43694; and dolasetron, formerly MDL 73147EF), with comparable clinical ef®cacy, are commercially available for these indications. The mechanism of the anti-emetic effect is not fully understood. 4 It is ascribed in part to central effects on the 5-HT 3 receptors in the area postrema, where the chemoreceptor trigger zone is located, with neural connections to the vomiting centre, but also in part to the peripheral action on 5-HT 3 receptors of afferent vagal ®bres in the stomach and small bowel.4±8 It has been suggested that the anti-emetic effect of 5-HT 3 may not only be due to suppression of nausea and the vomiting re¯ex, but also to direct or indirect effects on gastric motility. Although evidence for this latter assumption has been found in several animal SUMMARY Background: In previous studies, tropisetron has been shown to accelerate gastric emptying of a solid meal. However, it is uncertain whether other speci®c 5-hydroxytryptamine-3 receptor antagonists, such as ondansetron, also have a gastroprokinetic effect in humans. Aim: To evaluate the effect of ondansetron on gastric half-emptying time (T 1/2 ) of a solid meal, gastric myoelectrical activity and hormone levels in 14 healthy volunteers. Methods: In a placebo-controlled, randomized, crossover study, we investigated the effects of ondansetron (8 mg intravenously) on the gastric emptying of solids (by scintigraphy), gastric myoelectrical activity (by