An entire exon 3 germ-line rearrangement in the BRCA2 gene: pathogenic relevance of exon 3 deletion in breast cancer predisposition

<p>Abstract</p> <p>Background</p> <p>Germ-line mutations in the <it>BRCA1 </it>and <it>BRCA2 </it>genes are major contributors to hereditary breast/ovarian cancer. Large rearrangements are less frequent in the <it>BRCA2 </it>gene than in <it>BRCA1</it>. We report, here, the first total deletion of exon 3 in the <it>BRCA2 </it>gene that was detected during screening of 2058 index cases from breast/ovarian cancer families for <it>BRCA2 </it>large rearrangements. Deletion of exon 3, which is in phase, does not alter the reading frame. Low levels of alternative transcripts lacking exon 3 (Δ3 delta3 transcript) have been reported in normal tissues, which raises the question whether deletion of exon 3 is pathogenic.</p> <p>Methods</p> <p>Large <it>BRCA2 </it>rearrangements were analysed by QMPSF (Quantitative Multiplex PCR of Short Fluorescent Fragments) or MLPA (Multiplex Ligation-Dependent Probe Amplification). The exon 3 deletion was characterized with a "zoom-in" dedicated CGH array to the <it>BRCA2 </it>gene and sequencing. To determine the effect of exon 3 deletion and assess its pathogenic effect, three methods of transcript quantification were used: fragment analysis of FAM-labelled PCR products, specific allelic expression using an intron 2 polymorphism and competitive quantitative RT-PCR.</p> <p>Results</p> <p>Large rearrangements of <it>BRCA2 </it>were detected in six index cases out of 2058 tested (3% of all deleterious <it>BRCA2 </it>mutations). This study reports the first large rearrangement of the <it>BRCA2 </it>gene that includes all of exon 3 and leads to an <it>in frame </it>deletion of exon 3 at the transcriptional level. Thirty five variants in exon 3 and junction regions of <it>BRCA2 </it>are also reported, that contribute to the interpretation of the pathogenicity of the deletion. The quantitative approaches showed that there are three classes of delta3 <it>BRCA2 </it>transcripts (low, moderate and exclusive). Exclusive expression of the delta3 transcript by the mutant allele and segregation data provide evidence for a causal effect of the exon 3 deletion.</p> <p>Conclusion</p> <p>This paper highlights that large rearrangements and total deletion of exon 3 in the <it>BRCA2 </it>gene could contribute to hereditary breast and/or ovarian cancer. In addition, our findings suggest that, to interpret the pathogenic effect of any variants of exon 3, both accurate transcript quantification and co-segregation analysis are required.</p

An original phylogenetic approach identified mitochondrial haplogroup T1a1 as inversely associated with breast cancer risk in BRCA2 mutation carriers

Introduction: Individuals carrying pathogenic mutations in the BRCA1 and BRCA2 genes have a high lifetime risk of breast cancer. BRCA1 and BRCA2 are involved in DNA double-strand break repair, DNA alterations that can be caused by exposure to reactive oxygen species, a main source of which are mitochondria. Mitochondrial genome variations affect electron transport chain efficiency and reactive oxygen species production. Individuals with different mitochondrial haplogroups differ in their metabolism and sensitivity to oxidative stress. Variability in mitochondrial genetic background can alter reactive oxygen species production, leading to cancer risk. In the present study, we tested the hypothesis that mitochondrial haplogroups modify breast cancer risk in BRCA1/2 mutation carriers. Methods: We genotyped 22,214 (11,421 affected, 10,793 unaffected) mutation carriers belonging to the Consortium of Investigators of Modifiers of BRCA1/2 for 129 mitochondrial polymorphisms using the iCOGS array. Haplogroup inference and association detection were performed using a phylogenetic approach. ALTree was applied to explore the reference mitochondrial evolutionary tree and detect subclades enriched in affected or unaffected individuals. Results: We discovered that subclade T1a1 was depleted in affected BRCA2 mutation carriers compared with the rest of clade T (hazard ratio (HR) = 0.55; 95% confidence interval (CI), 0.34 to 0.88; P = 0.01). Compared with the most frequent haplogroup in the general population (that is, H and T clades), the T1a1 haplogroup has a HR of 0.62 (95% CI, 0.40 to 0.95; P = 0.03). We also identified three potential susceptibility loci, including G13708A/rs28359178, which has demonstrated an inverse association with familial breast cancer risk. Conclusions: This study illustrates how original approaches such as the phylogeny-based method we used can empower classical molecular epidemiological studies aimed at identifying association or risk modification effects.Peer reviewe

Contrasted mediolateral postural control mechanisms in varied foot positions.

International audienc

Advantages and disadvantages of stiffness instructions when studying postural control

To understand the maintenance of upright stance, researchers try to discover the fundamental mechanisms and attentional resources devoted to postural control and eventually to the performance of other tasks (e.g., counting in the head). During their studies, some researchers require participants to stand as steady as possible and other simply ask participants to stand naturally. Surprisingly, a clear and direct explanation of the usefulness of the steadiness requirement seems to be lacking, both in experimental and methodological discussions. Hence, the objective of the present note was to provide advantages and disadvantages of this steadiness requirement in studies of postural control. The advantages may be to study fundamental postural control, to eliminate useless postural variability, to control spurious body motions and to control the participants' thoughts. As disadvantages, this steadiness requirement only leads to study postural control in unnatural upright stance, it changes the focus of attention (internal vs. external) and the nature of postural control (unconscious vs. conscious), it increases the difficulty of a supposedly easy control task and it eliminates or reduces the opportunity to record exploratory behaviors. When looking carefully at the four advantages of the steadiness requirement, one can believe that they are, in fact, more disadvantageous than advantageous. Overall therefore, this requirement seems illegitimate and it is proposed that researchers should not use it in the study of postural control. They may use this requirement only if they search to know the limit until which participants can consciously reduce their postural sway

Broad stance conditions change postural control and postural sway.

Intuitively, a broad stance (i.e., standing with the feet farther apart than usual) should significantly improve postural stability. However, this intuition was not confirmed in quiet stance. Hence, a motion analysis system (markers attached to the trunk and head) and a force platform were used to investigate 13 healthy, young adults who performed 8 trials in standard and broad stances. In broad stance, the medialateral center of pressure (COP) sway mean power frequency was expected to be greater, whereas the variability (standard deviation) of COP, head, and trunk sway and the mean velocity of head and trunk sway was expected to be significantly lower. Accordingly, adoption of a broad stance significantly increased the medialateral mean power frequency of COP sway; decreased the standard deviation of medialateral COP, trunk, and head sway; and decreased the medialateral mean velocity of head sway. A broad stance was also associated with lower variability for head and COP sways in the anteroposterior axis. Unexpectedly, an effect of trial repetition was found for the variability of medialateral trunk sway. This was probably due to the break halfway through the study. In practical terms, broad stance conditions can improve postural control in the medialateral and anteroposterior axes

Contrôle postural de patients parkinsoniens lors d’observations libres de larges images

Introduction Les patients parkinsoniens ont un contrôle postural moins efficace que les personnes témoins surtout face à des perturbations extérieures. Nous avons vérifié s’il en était de même lors d’observations libres de larges images. Nous supposions qu’ils tourneraient moins leur corps que les témoins pour maintenir un contrôle postural efficace. Matériel et méthodes Vingt-trois patients (77,79 ± 16,56 ans ; stade Hoehn et Yahr : 2,04 ± 0,36 ; sous médication) et vingt témoins ont réalisé trois tâches visuelles : regarder une cible fixe (contrôle) et explorer des images, soit sans but (observation), soit pour y localiser 5 cibles (recherche). Une plateforme de force, un système d’analyse du mouvement, un oculomètre mobile et un écran panoramique ont été utilisés. Résultats Les patients ont trouvé moins de cibles en recherche que les témoins. Avec leurs yeux, ils exploraient les images significativement plus loin que les témoins, ils réalisaient plus de fixations et de plus longues fixations que les témoins. Ils tournaient leur corps de la même façon que les témoins en recherche et significativement plus leur dos et cou en tâche d’observation. Pourtant, les patients n’oscillaient jamais plus que les témoins. Discussion–conclusion Comme attendu, les patients ont utilisé plus leurs yeux que les témoins pour explorer les images. De façon inattendue, les patients tournaient globalement plus leur corps que les témoins, surtout en tâche d’observation. De façon surprenante, les patients n’étaient pas déstabilisés par leur exploration visuelle. Leur performance visuelle devait donc être diminuée à cause d’une stratégie de fixation inadaptée

Peripheral neuropathy may not be the only fundamental reason explaining increased sway in diabetic individuals.

Individuals with diabetic neuropathy sway more than control individuals while standing. This review specifically evaluated whether peripheral sensory neuropathy can be the only fundamental reason accounting for significant increased sway within this population. Twenty-six experimental articles were selected using MEDLINE and reference lists of relevant articles. The articles chosen investigated kinematic data of postural behaviour in controls and individuals with diabetic neuropathy during stance. Results of literature were compared with four expectations related to the peripheral sensory neuropathy fundamental hypothesis. Consistent with the peripheral sensory neuropathy hypothesis, the literature showed that individuals with diabetic neuropathy sway more than controls in quiet stance and even more so if their visual or vestibular systems were perturbed. Inconsistent with the hypothesis, individuals with diabetic neuropathy are more destabilised than controls in conditions altering sensation of the feet and legs (standing on a sway-referenced surface). The review showed that the peripheral sensory neuropathy hypothesis may not be the only fundamental cause accounting for significant increased postural sway in individuals with diabetic neuropathy. Visual impairments and changes in postural coordination may explain the divergence between expectations and results. In order to develop interventions aimed at improving postural control in individuals with diabetic neuropathy, scientific exploration of these new expectations should be detailed. Also at the practical level, the review discussed which additional sensory information - at the level of the hands and feet - may be more beneficial in individuals with diabetic neuropathy to reduce their postural sway

Active vision task and postural control in healthy, young adults: Synergy and probably not duality

In upright stance, individuals sway continuously and the sway pattern in dual tasks (e.g. a cognitive task performed in upright stance) differs significantly from that observed during the control quiet stance task. The cognitive approach has generated models (limited attentional resources, U-shaped nonlinear interaction) to explain such patterns based on competitive sharing of attentional resources. The objective of the current manuscript was to review these cognitive models in the specific context of visual tasks involving gaze shifts toward precise targets (here called active vision tasks). The selection excluded the effects of early and late stages of life or disease, external perturbations, active vision tasks requiring head and body motions and the combination of two tasks performed together (e.g. a visual task in addition to a computation in one's head). The selection included studies performed by healthy, young adults with control and active - difficult - vision tasks. Over 174 studies found in Pubmed and Mendeley databases, nine were selected. In these studies, young adults exhibited significantly lower amplitude of body displacement (center of pressure and/or body marker) under active vision tasks than under the control task. Furthermore, the more difficult the active vision tasks were, the better the postural control was. This underscores that postural control during active vision tasks may rely on synergistic relations between the postural and visual systems rather than on competitive or dual relations. In contrast, in the control task, there would not be any synergistic or competitive relations.SCOPUS: re.jinfo:eu-repo/semantics/publishe

Large lateral head movements and postural control.

International audienceRiccio and Stoffregen (1988) have suggested that task performance is the predominant constraint of change in postural control. To test this hypothesis, 12 healthy, young adults performed large lateral gaze shifts (left/right gaze shifts with a visual angle of 150° and at a frequency of 0.5 Hz or 1 Hz) and a control condition (looking at a stationary dot). Performance in the visual task was expected to be good under all conditions. In accordance with Riccio and Stoffregen's hypothesis, the center of pressure sway variability (range or standard deviation) was expected to be similar in the three visual tasks when a destabilizing, narrow stance was adopted. Indeed, body sway had to be restrained in narrow stance to adequately perform the task. In standard and wide stance conditions, the center of pressure sway variability was expected to be larger when gaze shifts were performed. Indeed, in these more stable stance conditions, the task could be performed successfully in minimizing energy expenditure, that is, in letting body sway increase naturally. The results were consistent with these expectations. On a practical level, intentional, large gaze shifts may not cause postural instability per se, even though postural sway may increase significantly

Large lateral head movements and postural control.

International audienceRiccio and Stoffregen (1988) have suggested that task performance is the predominant constraint of change in postural control. To test this hypothesis, 12 healthy, young adults performed large lateral gaze shifts (left/right gaze shifts with a visual angle of 150° and at a frequency of 0.5 Hz or 1 Hz) and a control condition (looking at a stationary dot). Performance in the visual task was expected to be good under all conditions. In accordance with Riccio and Stoffregen's hypothesis, the center of pressure sway variability (range or standard deviation) was expected to be similar in the three visual tasks when a destabilizing, narrow stance was adopted. Indeed, body sway had to be restrained in narrow stance to adequately perform the task. In standard and wide stance conditions, the center of pressure sway variability was expected to be larger when gaze shifts were performed. Indeed, in these more stable stance conditions, the task could be performed successfully in minimizing energy expenditure, that is, in letting body sway increase naturally. The results were consistent with these expectations. On a practical level, intentional, large gaze shifts may not cause postural instability per se, even though postural sway may increase significantly