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Leukodystrophies (LD) are rare inherited disorders that primarily affect the white matter (WM) of the central nervous system. The large heterogeneity of LD results from the diversity of the genetically determined defects that interfere with glial cells functions. Astrocytes have been identified as the primary target of LD with cystic myelin breakdown including those related to mutations in the ubiquitous translation initiation factor eIF2B. EIF2B is involved in global protein synthesis and its regulation under normal and stress conditions. Little is known about how eIF2B mutations have a major effect on WM. We performed a transcriptomic analysis using fibroblasts of 10 eIF2B-mutated patients with a severe phenotype and 10 age matched patients with other types of LD in comparison to control fibroblasts. ANOVA was used to identify genes that were statistically significantly differentially expressed at basal state and after ER-stress. The pattern of differentially expressed genes between basal state and ER-stress did not differ significantly among each of the three conditions. However, 70 genes were specifically differentially expressed in eIF2B-mutated fibroblasts whatever the stress conditions tested compared to controls, 96% being under-expressed. Most of these genes were involved in mRNA regulation and mitochondrial metabolism. The 13 most representative genes, including genes belonging to the Heterogeneous Nuclear Ribonucleoprotein (HNRNP) family, described as regulators of splicing events and stability of mRNA, were dysregulated during the development of eIF2B-mutated brains. HNRNPH1, F and C mRNA were over-expressed in foetus but under-expressed in children and adult brains. The abnormal regulation of HNRNP expression in the brain of eIF2B-mutated patients was concomitant with splicing dysregulation of the main genes involved in glial maturation such as PLP1 for oligodendrocytes and GFAP in astrocytes. These findings demonstrate a developmental deregulation of splicing events in glial cells that is related to abnormal production of HNRNP, in eIF2B-mutated brains.

A $d$-web ${\Cal W}(d)$ is given by $d$ complex analytic foliations of codimension $n$ in $({\sumbbb C}^N,0)$ such that the leaves are in general position. We are interested in the geometry of such configurations. A complex $({\Cal A}^{\bullet},\delta)$ of ${\sumbbb C}$-vector spaces is defined in which ${\Cal A}^0$ corresponds to functions and ${\Cal A}^p$ to $p$-forms of the web ${\Cal W}(d)$ for $1\leq p\leq n$. If $N=kn$ with $k\geq 2$, it is proved that $r_p:=\dim_{\,\sumbbb C}{\Cal A}^p$ is a finite analytic invariant of ${\Cal W}(d)$ with an optimal upper bound $\pi_{p}(d,k,n)$ for $0\leq p\leq n$. These bounds generalize the Castelnuovo?s ones for genus of curves in ${\sumbbb P}^{k}$ with degree $d$. Some characterization of the the space $H^0(V_n,\omega^p_{V_n})$ of abelian differentials to an algebraic variety $V_n$ in ${\sumbbb P}^{n+k-1}$ of pure dimension $n$ with degree $d$ is given. Moreover, using duality and Abel?s theorem, we investigate how for suitable $V_n$ the natural complex $\bigr(H^0(V_n,\omega^{\bullet}_{V_n}),d\,\bigr)$ and the abelian relation complex $({\Cal A}^{\bullet},\delta)$ of the linear web associated to $V_n$ in $({\sumbbb C}^{kn},0)$ are related. [ABSTRACT FROM AUTHOR]