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Gnathodiaphyseal dysplasia (GDD) is a rare skeletal syndrome characterized by bone fragility, sclerosis of tubular bones, and cemento-osseous lesions of the jawbone. By linkage analysis of a large Japanese family with GDD, we previously mapped the GDD locus to chromosome 11p14.3-15.1. In the critical region determined by recombination mapping, we identified a novel gene (GDD1) that encodes a 913-amino-acid protein containing eight putative transmembrane-spanning domains. Two missense mutations (C356R and C356G) of GDD1 were identified in the two families with GDD (the original Japanese family and a new African American family), and both missense mutations occur at the cysteine residue at amino acid 356, which is evolutionarily conserved among human, mouse, zebrafish, fruit fly, and mosquito. Cellular localization to the endoplasmic reticulum suggests a role for GDD1 in the regulation of intracellular calcium homeostasis.

We compared the mechanisms of apolipoprotein E- (apoE-) and antioxidant- (AO-) mediated inhibition of beta-amyloid fibril (fA beta) formation in vitro, based on a nucleation-dependent polymerization model using fluorescence spectroscopy with thioflavin T. We first applied a kinetic plot to transform a sigmoidal time-course curve of fA beta formation from freshly prepared amyloid beta-peptides (A beta) into a straight line. Mathematical treatment of this plot demonstrated that the above-described sigmoidal curve is a logistic curve and provided us with a kinetic parameter t(1/2), the time when the rate of fA beta formation is maximum. t(1/2) of beta-amyloids (A beta) (1-42) and (1-40) were 18.7 +/- 1.7 min and 6.3 +/- 0.2 h, respectively (mean +/- SD, n = 3) and were independent of the initial A beta concentration examined. Although apoE extended t(1/2) of both A betas in a dose-dependent manner, AO did not. On the other hand, the final amount of fA beta formed was decreased by both apoE and AO dose-dependently. We then analyzed the effect of apoE and AO on the extension reaction of fA beta, based on a first-order kinetic model. Although apoE extended the time to proceed to equilibrium in a dose-dependent manner, AO did not. On the other hand, both apoE and AO dose-dependently decreased the final amount of fA beta formed. These results indicate that apoE and AO inhibit fA beta formation in vitro by different mechanisms and suggest the existence of multiple pharmacological targets for the prevention of fA beta formation.

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