Hypoglycosylation and reduced laminin-binding activity of α-dystroglycan are common characteristics of dystroglycanopathy, which is a group of congenital and limb-girdle muscular dystrophies. Fukuyama-type congenital muscular dystrophy (FCMD), caused by a mutation in the fukutin gene, is a severe form of dystroglycanopathy. A retrotransposal insertion in fukutin is seen in almost all cases of FCMD. To better understand the molecular pathogenesis of dystroglycanopathies and to explore therapeutic strategies, we generated knock-in mice carrying the retrotransposal insertion in the mouse fukutin ortholog. Knock-in mice exhibited hypoglycosylated α-dystroglycan; however, no signs of muscular dystrophy were observed. More sensitive methods detected minor levels of intact α-dystroglycan, and solid-phase assays determined laminin binding levels to be ∼50% of normal. In contrast, intact α-dystroglycan is undetectable in the dystrophic Largemyd mouse, and laminin-binding activity is markedly reduced. These data indicate that a small amount of intact α-dystroglycan is sufficient to maintain muscle cell integrity in knock-in mice, suggesting that the treatment of dystroglycanopathies might not require the full recovery of glycosylation. To examine whether glycosylation defects can be restored in vivo, we performed mouse gene transfer experiments. Transfer of fukutin into knock-in mice restored glycosylation of α-dystroglycan. In addition, transfer of LARGE produced laminin-binding forms of α-dystroglycan in both knock-in mice and the POMGnT1 mutant mouse, which is another model of dystroglycanopathy. Overall, these data suggest that even partial restoration of α-dystroglycan glycosylation and laminin-binding activity by replacing or augmenting glycosylation-related genes might effectively deter dystroglycanopathy progression and thus provide therapeutic benefits.

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The genetic factors underlying mental retardation (MR) are very heterogeneous. Recent studies have identified a number of genes involved in MR, several of which lie on the X-chromosome, but the current understanding of the monogenic causes of MR is far from complete. Investigation of chromosomal rearrangements in patients with MR has proven particularly informative in the search for novel genes. Using array-based comparative genomic hybridization analysis, we identified a small copy number gain at Xq25, which was undetectable by conventional G-band analysis, in a boy with unexplained MR. Further characterization revealed a partial tandem duplication of GRIA3, an alteration also present on one allele in his mother. RT-PCR analysis of lymphoblastoid cell RNA revealed remarkably reduced GRIA3 transcript levels in the patient. The mother, whose cognitive level is normal, also demonstrated remarkably reduced GRIA3 transcript levels in lymphoblastoid cells, and X-chromosome inactivation (XCI) was completely skewed in her peripheral lymphocytes. It is possible that XCI in the brain is not completely skewed and that GRIA3 expression from the normal allele may account for the mother's normal cognitive function. Taken together with previous findings of GRIA3 disruptions in the patients with MR, our study strengthens the idea that GRIA3 is a candidate gene for X-linked MR and that severely reduced GRIA3 expression results in MR.

Lignin is one of the most abundant biomasses in nature. It is composed of aromatic moieties and has great potential for use in the production of chemical alternatives to petroleum products. Because of increasing interest in biocatalysis, the potential for industrial application of microbial metabolism of lignin-derived compounds has gained considerable recent attention. Functional screenings of culturable bacteria isolated from sediments and sunken wood collected from the deep sea revealed the existence of a number of previously unidentified bacteria capable of metabolizing lignin-related aromatic compounds. Of the 510 isolates obtained in the present study, 208 completely or partially metabolized these compounds. The 208 isolates were classified into diverse phyla, including Firmicutes, Actinobacteria, Bacteroidetes, and Proteobacteria. Among the 208 isolates, 61 unique 16S rRNA gene sequences were detected including previously unidentified marine lineage isolates. The metabolites of the isolates were analysed using liquid chromatography/mass spectrometry (LC/MS) or gas chromatography/mass spectrometry (GC/MS). Most of the representative 61 isolates non-oxidatively decarboxylated the substrates to produce the corresponding aromatic vinyl monomers, which are used as feed stocks for bio-based plastics production. Oxidative metabolism of the lignin-related compounds for assimilation was frequently observed. Our study showed that the deep-sea environment contains an abundance of microorganisms capable of both non-oxidative and oxidative bioconversion of lignin-derived aromatic compounds. The ability for bio-conversion of aromatic compounds found in this study will facilitate the development of future biotechnological applications

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