Molecular Consequences of the SERPINH1/HSP47 Mutation in the Dachshund Natural Model of Osteogenesis Imperfecta.

Osteogenesis imperfecta (OI) is a heritable connective tissue disease characterized by bone fragility and increased risk of fractures. Up to now, mutations in at least 18 genes have been associated with dominant and recessive forms of OI that affect the production or post-translational processing of procollagen or alter bone homeostasis. Among those, SERPINH1 encoding heat shock protein 47 (HSP47), a chaperone exclusive for collagen folding in the ER, was identified to cause a severe form of OI in dachshunds (L326P) as well as in humans (one single case with a L78P mutation). To elucidate the disease mechanism underlying OI in the dog model, we applied a range of biochemical assays to mutant and control skin fibroblasts as well as on bone samples. These experiments revealed that type I collagen synthesized by mutant cells had decreased electrophoretic mobility. Procollagen was retained intracellularly with concomitant dilation of ER cisternae and activation of the ER stress response markers GRP78 and phospho-eIF2α, thus suggesting a defect in procollagen processing. In line with the migration shift detected on SDS-PAGE of cell culture collagen, extracts of bone collagen from the OI dog showed a similar mobility shift, and on tandem mass spectrometry, the chains were post-translationally overmodified. The bone collagen had a higher content of pyridinoline than control dog bone. We conclude that the SERPINH1 mutation in this naturally occurring model of OI impairs how HSP47 acts as a chaperone in the ER. This results in abnormal post-translational modification and cross-linking of the bone collagen.

The Impact of Language Opacity and Proficiency on Reading Strategies in Bilinguals: An Eye Movement Study

Reading strategies vary across languages according to orthographic depth - the complexity of the grapheme in relation to phoneme conversion rules - notably at the level of eye movement patterns. We recently demonstrated that a group of early bilinguals, who learned both languages equally under the age of seven, presented a first fixation location (FFL) closer to the beginning of words when reading in German as compared with French. Since German is known to be orthographically more transparent than French, this suggested that different strategies were being engaged depending on the orthographic depth of the used language. Opaque languages induce a global reading strategy, and transparent languages force a local/serial strategy. Thus, pseudo-words were processed using a local strategy in both languages, suggesting that the link between word forms and their lexical representation may also play a role in selecting a specific strategy. In order to test whether corresponding effects appear in late bilinguals with low proficiency in their second language (L2), we present a new study in which we recorded eye movements while two groups of late German-French and French-German bilinguals read aloud isolated French and German words and pseudo-words. Since, a transparent reading strategy is local and serial, with a high number of fixations per stimuli, and the level of the bilingual participants' L2 is low, the impact of language opacity should be observed in L1. We therefore predicted a global reading strategy if the bilinguals' L1 was French (FFL close to the middle of the stimuli with fewer fixations per stimuli) and a local and serial reading strategy if it was German. Thus, the L2 of each group, as well as pseudo-words, should also require a local and serial reading strategy. Our results confirmed these hypotheses, suggesting that global word processing is only achieved by bilinguals with an opaque L1 when reading in an opaque language; the low level in the L2 gives way to a local and serial reading strategy. These findings stress the fact that reading behavior is influenced not only by the linguistic mode but also by top-down factors, such as readers' proficiency.