Hemophiliacs A patients from Algeria without mutation or rearrangement in the F8 gene

Hemophilia A (HA) is the most severe X-linked inherited bleeding disorder caused by hemizygous mutations in the F8 gene. Several F8 mutations are responsible of HA including intron 1 and 22 micro-inversions, large and small deletions, insertions, duplications, and point mutations. In a previous study, we determined the molecular causes of HA in 85% of patients group studied. However, no mutation were found in three unrelated patients origi-nating from Western Algeria. In the present study, we sought to characterize the molecular origin of HA in three patients by investigating rearrangements in the F8 gene using the MLPA method. Comparaison between case results and healthy controls showed absence of deletions or duplications in the F8 gene in these three hemophiliacs A patients. This finding has already been reported in many studies where any F8 mutation or rearrangement has been identified. Further analysis are required in order to determine the molecular origin of the disease in these families. It would be very interesting to look for deep intonic mutations and to study epigenetic mechanisms as well as DNA methylation and miRNAs.

Molecular Origin of Fast Evaporation at the Solid–water–vapor Line in a Sessile Droplet

By analyzing the behaviors of water molecules at the solid–water–vapor contact line, we explore the molecular origins of large evaporation rates at the contact line and find new ways to...

Nanoscale organization of Nicastrin, the substrate receptor of the γ-secretase complex, as independent molecular domains

Alterations in the canonical processing of Amyloid Precursor Protein generate proteoforms that contribute to the onset of Alzheimer’s Disease. Modified composition of γ-secretase or mutations in its subunits has been directly linked to altered generation of Amyloid beta. Despite biochemical evidence about the role of γ-secretase in the generation of APP, the molecular origin of how spatial heterogeneity in the generation of proteoforms arises is not well understood. Here, we evaluated the localization of Nicastrin, a γ-secretase subunit, at nanometer sized functional zones of the synapse. With the help of super resolution microscopy, we confirm that Nicastrin is organized into nanodomains of high molecular density within an excitatory synapse. A similar nanoorganization was also observed for APP and the catalytic subunit of γ-secretase, Presenilin 1, that were discretely associated with Nicastrin nanodomains. Though Nicastrin is a functional subunit of γ-secretase, the Nicastrin and Presenilin1 nanodomains were either colocalized or localized independent of each other. The Nicastrin and Presenilin domains highlight a potential independent regulation of these molecules different from their canonical secretase function. The collisions between secretases and substrate molecules decide the probability and rate of product formation for transmembrane proteolysis. Our observations of secretase nanodomains indicate a spatial difference in the confinement of substrate and secretases, affecting the local probability of product formation by increasing their molecular availability, resulting in differential generation of proteoforms even within single synapses.