Mutations in the ribosomal protein gene RPL10 suggest a novel modulating disease mechanism for autism.

Autism has a strong genetic background with a higher frequency of affected males suggesting involvement of X-linked genes and possibly also other factors causing the unbalanced sex ratio in the etiology of the disorder. We have identified two missense mutations in the ribosomal protein gene RPL10 located in Xq28 in two independent families with autism. We have obtained evidence that the amino-acid substitutions L206M and H213Q at the C-terminal end of RPL10 confer hypomorphism with respect to the regulation of the translation process while keeping the basic translation functions intact. This suggests the contribution of a novel, possibly modulating aberrant cellular function operative in autism. Previously, we detected high expression of RPL10 by RNA in situ hybridization in mouse hippocampus, a constituent of the brain limbic system known to be afflicted in autism. Based on these findings, we present a model for autistic disorder where a change in translational function is suggested to impact on those cognitive functions that are mediated through the limbic system.

A point mutation in the IL-12R beta 2 gene underlies the IL-12 unresponsiveness of Lps-defective C57BL/10ScCr mice.

Lps-defective C57BL/10ScCr (Cr) mice are homozygous for a deletion encompassing Toll-like receptor 4 that makes them refractory to the biological activity of LPS. In addition, these mice exhibit an inherited IL-12 unresponsiveness resulting in impaired IFN-gamma responses to different microorganisms. By positional cloning methods, we show here that this second defect of Cr mice is due to a mutation in a single gene located on mouse chromosome 6, in close proximity to the Igkappa locus. The gene is IL-12Rbeta2. Cr mice carry a point mutation creating a stop codon that is predicted to cause premature termination of the translated IL-12Rbeta2 after a lysine residue at position 777. The truncated beta2 chain can still form a heterodimeric IL-12R that allows phosphorylation of Janus kinase 2, but, unlike the wild-type IL-12R, can no longer mediate phosphorylation of STAT4. Because the phosphorylation of STAT4 is a prerequisite for the IL-12-mediated induction of IFN-gamma, its absence in Cr mice is responsible for their defective IFN-gamma response to microorganisms.

Predetermined chromosomal deletion encompassing the Nf-1 gene.

Complex chromosomal rearrangements (deletions, inversions, translocations) are a hallmark of human tumour cells. Yet, the generation of animal models for gross chromosomal abnormalities still presents a formidable challenge. Here, we describe a versatile procedure for chromosomal engineering that was used to generate an ES cell line with a megabase deletion encompassing the tumour suppressor gene neurofibromatosis-1 (Nf-1) on mouse chromosome 11, which is often deleted in tumours of neural crest origin. Homologous recombination into sites flanking Nf-1 was used to introduce artificial sequences (triple-helix, loxP, vector backbone) that can be employed for in vitro recovery of intervening sequences or the generation of in vivo deletions. This strategy may be developed into a scheme by which large chromosomal regions with precisely defined end points may be excised from mammalian cells and reintroduced after suitable in vitro modification.

A yeast artificial chromosome contig spanning the mouse immunoglobulin kappa light chain locus.

A single contig spanning the entire mouse immunoglobulin kappa light chain (Igk) locus on chromosome 6 has been established using yeast and bacterial artificial chromosome clones. Detailed mapping of the Igk locus indicates that a member of the Igk-V2 gene family, located about 3.5 megabases upstream of the Igk-J-C complex, is the most distal functional Igk-V gene. Sequence analyses of Igk-V genes and anonymous DNA segments provide indications for internal duplications at the 5' end of the Igk-V locus and identify the likely origin of Igk-V orphon gene clusters located elsewhere in the mouse genome.

Silver concentrations in human tissues. their dependence on dental amalgam and other factors.

Human tissue samples (liver, kidney cortex, 5 brain regions: grey matter of cerebrum, white matter of cerebrum, nucleus lentiformis, cerebellum, brain stem) from 173 decreased persons were analysed for silver (Ag) by GF-AAS (Graphite Furnace Atomic Absorption Spectrometry) and the results compared with the number of teeth with amalgam fillings and the concentration of inorganic mercury (Hg), which had been determined in the same tissue samples in a previous study. It was found that the mean Ag concentrations in liver and brain of adult females are approximately twice that of males. Moreover, the Ag concentrations, especially in the brain, depend possibly on age. To exclude these confounding factors as far as possible, the influence of dental amalgam and the correlation of Ag and Hg were evaluated only in a sub-group of 93 males, aged 11-50 years. In this sub-group statistically significant correlations were found between the number of teeth with dental amalgam and the Ag concentrations in the cerebral cortex and the liver. No such correlation was found for the kidney. Ag and inorg. Hg correlate well in this sub-group in the liver, but not in the cerebral cortex or the kidney. Individuals from this sub-group with (i) 0-2 and with (ii) more than 9 teeth with amalgam fillings show mean Ag concentrations (micrograms/kg in tissue wet weight, geom. mean) of 1.59 and 5.41 in the grey matter of cerebrum, 1.42 and 4.25 in the white matter of cerebrum, 1.53 and 4.89 in the nucleus lentiformis, 1.95 and 5.02 in the cerebellum, 1.05 and 3.27 in the brain stem, 3.40 and 8.15 in the liver and 0.42 and 0.44 in the kidney cortex. In contrast, comparing all individuals under investigation with only 0-2 teeth with amalgam no correlation between Ag and inorg. Hg could be found in liver, kidney cortex or cerebral cortex. These results show that amalgam fillings release Ag as well. Considering the different toxicokinetics of Ag and Hg it can be concluded that Ag is a reliable marker for the fact that the elevated concentrations of inorg. Hg found in tissues of individuals with amalgam fillings derive mainly from these fillings and not from other theoretically possible sources.

Mercury burden of human fetal and infant tissues.

UNLABELLED: The total mercury concentrations in the liver (Hg-L), the kidney cortex (Hg-K) and the cerebral cortex (Hg-C) of 108 children aged 1 day-5 years, and the Hg-K and Hg-L of 46 fetuses were determined. As far as possible, the mothers were interviewed and their dental status was recorded. The results were compared to mercury concentrations in the tissues of adults from the same geographical area. The Hg-K (n = 38) and Hg-L (n = 40) of fetuses and Hg-K (n = 35) and Hg-C (n = 35) of older infants (11-50 weeks of life) correlated significantly with the number of dental amalgam fillings of the mother. The toxicological relevance of the unexpected high Hg-K of older infants from mothers with higher numbers of dental amalgam fillings is discussed. CONCLUSION: Future discussion on the pros and cons of dental amalgam should not be limited to adults or children with their own amalgam fillings, but also include fetal exposure. The unrestricted application of amalgam for dental restorations in women before and during the child-bearing age should be reconsidered.