Role of MAPT mutations and haplotype in frontotemporal lobar degeneration in Northern Finland

<p>Abstract</p> <p>Background</p> <p>Frontotemporal lobar degeneration (FTLD) consists of a clinically and neuropathologically heterogeneous group of syndromes affecting the frontal and temporal lobes of the brain. Mutations in microtubule-associated protein tau (<it>MAPT</it>), progranulin (<it>PGRN</it>) and charged multi-vesicular body protein 2B (<it>CHMP2B</it>) are associated with familial forms of the disease. The prevalence of these mutations varies between populations. The H1 haplotype of <it>MAPT </it>has been found to be closely associated with tauopathies and with sporadic FTLD. Our aim was to investigate <it>MAPT </it>mutations and haplotype frequencies in a clinical series of patients with FTLD in Northern Finland.</p> <p>Methods</p> <p><it>MAPT </it>exons 1, 2 and 9–13 were sequenced in 59 patients with FTLD, and <it>MAPT </it>haplotypes were analysed in these patients, 122 patients with early onset Alzheimer's disease (eoAD) and 198 healthy controls.</p> <p>Results</p> <p>No pathogenic mutations were found. The H2 allele frequency was 11.0% (<it>P </it>= 0.028) in the FTLD patients, 9.8% (<it>P </it>= 0.029) in the eoAD patients and 5.3% in the controls. The H2 allele was especially clustered in patients with a positive family history (<it>P </it>= 0.011) but did not lower the age at onset of the disease. The ApoE4 allele frequency was significantly increased in the patients with eoAD and in those with FTLD.</p> <p>Conclusion</p> <p>We conclude that although pathogenic <it>MAPT </it>mutations are rare in Northern Finland, the <it>MAPT </it>H2 allele may be associated with increased risks of FTLD and eoAD in the Finnish population.</p

Large-scale association analysis provides insights into the genetic architecture and pathophysiology of type 2 diabetes

To extend understanding of the genetic architecture and molecular basis of type 2 diabetes (T2D), we conducted a meta-analysis of genetic variants on the Metabochip involving 34,840 cases and 114,981 controls, overwhelmingly of European descent. We identified ten previously unreported T2D susceptibility loci, including two demonstrating sex-differentiated association. Genome-wide analyses of these data are consistent with a long tail of further common variant loci explaining much of the variation in susceptibility to T2D. Exploration of the enlarged set of susceptibility loci implicates several processes, including CREBBP-related transcription, adipocytokine signalling and cell cycle regulation, in diabetes pathogenesis

Isoreticular Metalation of Metal-Organic Frameworks

Sequential covalent transformation and metalation were performed on (Zn(4)O)(3)(BDC-NH(2))(3)(BTB)(4) with maintenance of crystallinity and porosity. Reaction of (Zn(4)O)(3)(BDC-NH(2))(3)(BTB)(4) with 2-pyridinecarboxaldehyde in toluene at room temperature for 5 days resulted in the formation of the extended crystalline structure (Zn(4)O)(3)(BDC-C(6)H(5)N(2))(3)(BTB)(4), which possesses iminopyridine moieties covalently bound to the organic links of the framework. Subsequent reaction with PdCl(2)(CH(3)CN)(2) in CH(2)Cl(2) at room temperature for 12 h yielded the metalated metal-organic framework (Zn(4)O)(3)(BDC-C(6)H(5)N(2)PdCl(2))(3)(BTB)(4). Both functionalized materials retained high crystallinity and were permanently porous with high surface areas [3200 and 1700 m(2) g(-1) for (Zn(4)O)(3)(BDC-C(6)H(5)N(2))(3)(BTB)(4) and (Zn(4)O)(3)(BDC-C(6)H(5)N(2)PdCl(2))(3)(BTB)(4), respectively.].Christian J. Doonan, William Morris, Hiroyasu Furukawa, and Omar M. Yagh

A unique gene expression signature discriminates familial Alzheimer's disease mutation carriers from their wild-type siblings

Alzheimer's disease (AD) is a neurodegenerative disease with an insidious onset and progressive course that inevitably leads to death. The current diagnostic tools do not allow for diagnosis until the disease has lead to irreversible brain damage. Genetic studies of autosomal dominant early onset familial AD has identified three causative genes: amyloid precursor protein (APP), presenilin 1 and 2 (PSEN1 and PSEN2). We performed a global gene expression analysis on fibroblasts from 33 individuals (both healthy and demented mutation carriers as well as wild-type siblings) from three families segregating the APP(SWE), APP(ARC) and PSEN1 H163Y mutations, respectively. The mutations cause hereditary progressive cognitive disorder, including typical autosomal dominant AD. Our data show that the mutation carriers share a common gene expression profile significantly different from that of their wild-type siblings. The results indicate that the disease process starts several decades before the onset of cognitive decline, suggesting that presymptomatic diagnosis of AD and other progressive cognitive disorders may be feasible in the near future

Synthesis of N-Heterocyclic Carbene Stabilized Catecholatoborenium Cations by Ligand Substitution

Ligand substitution is not a common procedure for the preparation of different borenium cations. This work demonstrates that the chloride ligands of several NHC-stabilized dichloroborenium cations [NHC·BCl2][X] (NHC = (R′C)2(NR)2C; 1, R = iPr, R′ = H; 2, R = iPr, R′ = Me; 3, R = tBu, R′ = H; X = AlCl4, B(3,5-Cl2-C6H3)4) could be replaced with a catecholato moiety to produce [NHC·Bcat][X]. According to single-crystal X-ray analyses this particular ligand exchange enhanced the Lewis acidity of the target borocations with respect to the dichloro precursors.ASTAR (Agency for Sci., Tech. and Research, S’pore)Accepted versio