Genome-wide meta-analyses identify novel loci associated with n-3 and n-6 polyunsaturated fatty acid levels in Chinese and European-ancestry populations
Epidemiological studies suggest that levels of n-3 and n-6 long-chain polyunsaturated fatty acids are associated with risk of cardio-metabolic outcomes across different ethnic groups. Recent genome-wide association studies in populations of European ancestry have identified several loci associated with plasma and/or erythrocyte polyunsaturated fatty acids. To identify additional novel loci, we carried out a genome-wide association study in two population-based cohorts consisting of 3521 Chinese participants, followed by a trans-ethnic meta-analysis with meta-analysis results from 8962 participants of European ancestry. Fou...
Source: Human Molecular Genetics - February 23, 2016 Category: Genetics & Stem Cells Authors: Hu, Y., Li, H., Lu, L., Manichaikul, A., Zhu, J., Chen, Y.-D. I., Sun, L., Liang, S., Siscovick, D. S., Steffen, L. M., Tsai, M. Y., Rich, S. S., Lemaitre, R. N., Lin, X. Tags: ASSOCIATION STUDIES ARTICLES Source Type: research
Identification of a novel susceptibility locus at 13q34 and refinement of the 20p12.2 region as a multi-signal locus associated with bladder cancer risk in individuals of European ancestry
Candidate gene and genome-wide association studies (GWAS) have identified 15 independent genomic regions associated with bladder cancer risk. In search for additional susceptibility variants, we followed up on four promising single-nucleotide polymorphisms (SNPs) that had not achieved genome-wide significance in 6911 cases and 11 814 controls (rs6104690, rs4510656, rs5003154 and rs4907479, P < 1 x 10–6), using additional data from existing GWAS datasets and targeted genotyping for studies that did not have GWAS data. In a combined analysis, which included data on up to 15 058 cases and 286 270 controls, two SNPs a...
Source: Human Molecular Genetics - February 23, 2016 Category: Genetics & Stem Cells Authors: Figueroa, J. D., Middlebrooks, C. D., Banday, A. R., Ye, Y., Garcia-Closas, M., Chatterjee, N., Koutros, S., Kiemeney, L. A., Rafnar, T., Bishop, T., Furberg, H., Matullo, G., Golka, K., Gago-Dominguez, M., Taylor, J. A., Fletcher, T., Siddiq, A., Cortess Tags: ASSOCIATION STUDIES ARTICLES Source Type: research
Genetic overexpression of Serpina3n attenuates muscular dystrophy in mice
Muscular dystrophy (MD) is associated with mutations in genes that stabilize the myofiber plasma membrane, such as through the dystrophin–glycoprotein complex (DGC). Instability of this complex or defects in membrane repair/integrity leads to calcium influx and myofiber necrosis leading to progressive dystrophic disease. MD pathogenesis is also associated with increased skeletal muscle protease levels and activity that could augment weakening of the sarcolemma through greater degradation of cellular attachment complexes. Here, we observed a compensatory increase in the serine protease inhibitor Serpina3n in mouse mod...
Source: Human Molecular Genetics - February 23, 2016 Category: Genetics & Stem Cells Authors: Tjondrokoesoemo, A., Schips, T., Kanisicak, O., Sargent, M. A., Molkentin, J. D. Tags: ARTICLES Source Type: research
Keratin 12 missense mutation induces the unfolded protein response and apoptosis in Meesmann epithelial corneal dystrophy
Meesmann epithelial corneal dystrophy (MECD) is a rare autosomal dominant disorder caused by dominant-negative mutations within the KRT3 or KRT12 genes, which encode the cytoskeletal protein keratins K3 and K12, respectively. To investigate the pathomechanism of this disease, we generated and phenotypically characterized a novel knock-in humanized mouse model carrying the severe, MECD-associated, K12-Leu132Pro mutation. Although no overt changes in corneal opacity were detected by slit-lamp examination, the corneas of homozygous mutant mice exhibited histological and ultrastructural epithelial cell fragility phenotypes. An...
Source: Human Molecular Genetics - February 23, 2016 Category: Genetics & Stem Cells Authors: Allen, E. H. A., Courtney, D. G., Atkinson, S. D., Moore, J. E., Mairs, L., Poulsen, E. T., Schiroli, D., Maurizi, E., Cole, C., Hickerson, R. P., James, J., Murgatroyd, H., Smith, F. J. D., MacEwen, C., Enghild, J. J., Nesbit, M. A., Leslie Pedrioli, D. Tags: ARTICLES Source Type: research
Loss of HCN1 enhances disease progression in mouse models of CNG channel-linked retinitis pigmentosa and achromatopsia
Most inherited blinding diseases are characterized by compromised retinal function and progressive degeneration of photoreceptors. However, the factors that affect the life span of photoreceptors in such degenerative retinal diseases are rather poorly understood. Here, we explore the role of hyperpolarization-activated cyclic nucleotide-gated channel 1 (HCN1) in this context. HCN1 is known to adjust retinal function under mesopic conditions, and although it is expressed at high levels in rod and cone photoreceptor inner segments, no association with any retinal disorder has yet been found. We investigated the effects of an...
Source: Human Molecular Genetics - February 23, 2016 Category: Genetics & Stem Cells Authors: Schön, C., Asteriti, S., Koch, S., Sothilingam, V., Garrido, M. G., Tanimoto, N., Herms, J., Seeliger, M. W., Cangiano, L., Biel, M., Michalakis, S. Tags: ARTICLES Source Type: research
Three-layered proteomic characterization of a novel ACTN4 mutation unravels its pathogenic potential in FSGS
This study illustrates the potential of genomics and complementary, high-resolution proteomics analyses to study the pathogenicity of rare gene variants. (Source: Human Molecular Genetics)
Source: Human Molecular Genetics - February 23, 2016 Category: Genetics & Stem Cells Authors: Bartram, M. P., Habbig, S., Pahmeyer, C., Höhne, M., Weber, L. T., Thiele, H., Altmüller, J., Kottoor, N., Wenzel, A., Krueger, M., Schermer, B., Benzing, T., Rinschen, M. M., Beck, B. B. Tags: ARTICLES Source Type: research
Gene network and familial analyses uncover a gene network involving Tbx5/Osr1/Pcsk6 interaction in the second heart field for atrial septation
Atrial septal defects (ASDs) are a common human congenital heart disease (CHD) that can be induced by genetic abnormalities. Our previous studies have demonstrated a genetic interaction between Tbx5 and Osr1 in the second heart field (SHF) for atrial septation. We hypothesized that Osr1 and Tbx5 share a common signaling networking and downstream targets for atrial septation. To identify this molecular networks, we acquired the RNA-Seq transcriptome data from the posterior SHF of wild-type, Tbx5+/–, Osr1+/–, Osr1–/– and Tbx5+/–/Osr1+/– mutant embryos. Gene set analysis was used to identif...
Source: Human Molecular Genetics - February 23, 2016 Category: Genetics & Stem Cells Authors: Zhang, K. K., Xiang, M., Zhou, L., Liu, J., Curry, N., Heine Suner, D., Garcia-Pavia, P., Zhang, X., Wang, Q., Xie, L. Tags: ARTICLES Source Type: research
Nf1+/- monocytes/macrophages induce neointima formation via CCR2 activation
Persons with neurofibromatosis type 1 (NF1) have a predisposition for premature and severe arterial stenosis. Mutations in the NF1 gene result in decreased expression of neurofibromin, a negative regulator of p21Ras, and increases Ras signaling. Heterozygous Nf1 (Nf1+/–) mice develop a marked arterial stenosis characterized by proliferating smooth muscle cells (SMCs) and a predominance of infiltrating macrophages, which closely resembles arterial lesions from NF1 patients. Interestingly, lineage-restricted inactivation of a single Nf1 allele in monocytes/macrophages is sufficient to recapitulate the phenotype observe...
Source: Human Molecular Genetics - February 23, 2016 Category: Genetics & Stem Cells Authors: Bessler, W. K., Kim, G., Hudson, F. Z., Mund, J. A., Mali, R., Menon, K., Kapur, R., Clapp, D. W., Ingram, D. A., Stansfield, B. K. Tags: ARTICLES Source Type: research
Sensory and autonomic deficits in a new humanized mouse model of familial dysautonomia
Familial dysautonomia (FD) is an autosomal recessive neurodegenerative disease that affects the development and survival of sensory and autonomic neurons. FD is caused by an mRNA splicing mutation in intron 20 of the IKBKAP gene that results in a tissue-specific skipping of exon 20 and a corresponding reduction of the inhibitor of kappaB kinase complex-associated protein (IKAP), also known as Elongator complex protein 1. To date, several promising therapeutic candidates for FD have been identified that target the underlying mRNA splicing defect, and increase functional IKAP protein. Despite these remarkable advances in dru...
Source: Human Molecular Genetics - February 23, 2016 Category: Genetics & Stem Cells Authors: Morini, E., Dietrich, P., Salani, M., Downs, H. M., Wojtkiewicz, G. R., Alli, S., Brenner, A., Nilbratt, M., LeClair, J. W., Oaklander, A. L., Slaugenhaupt, S. A., Dragatsis, I. Tags: ARTICLES Source Type: research
{alpha}-Synuclein interferes with the ESCRT-III complex contributing to the pathogenesis of Lewy body disease
In this study, we examined the role of the endosomal sorting complex required for transport (ESCRT) pathway on the propagation of α-syn. α-syn, which is transported via the ESCRT pathway through multivesicular bodies for degradation, can also target the degradation of the ESCRT protein-charged multivesicular body protein (CHMP2B), thus generating a roadblock of endocytosed α-syn. Disruption of the ESCRT transport system also resulted in increased exocytosis of α-syn thus potentially increasing cell-to-cell propagation of synuclein. Conversely, delivery of a lentiviral vector overexpressing CHMP2B re...
Source: Human Molecular Genetics - February 23, 2016 Category: Genetics & Stem Cells Authors: Spencer, B., Kim, C., Gonzalez, T., Bisquertt, A., Patrick, C., Rockenstein, E., Adame, A., Lee, S.-J., Desplats, P., Masliah, E. Tags: ARTICLES Source Type: research
Conserved pharmacological rescue of hereditary spastic paraplegia-related phenotypes across model organisms
Hereditary spastic paraplegias (HSPs) are a group of neurodegenerative diseases causing progressive gait dysfunction. Over 50 genes have now been associated with HSP. Despite the recent explosion in genetic knowledge, HSP remains without pharmacological treatment. Loss-of-function mutation of the SPAST gene, also known as SPG4, is the most common cause of HSP in patients. SPAST is conserved across animal species and regulates microtubule dynamics. Recent studies have shown that it also modulates endoplasmic reticulum (ER) stress. Here, utilizing null SPAST homologues in C. elegans, Drosophila and zebrafish, we tested FDA-a...
Source: Human Molecular Genetics - February 23, 2016 Category: Genetics & Stem Cells Authors: Julien, C., Lissouba, A., Madabattula, S., Fardghassemi, Y., Rosenfelt, C., Androschuk, A., Strautman, J., Wong, C., Bysice, A., O'sullivan, J., Rouleau, G. A., Drapeau, P., Parker, J. A., Bolduc, F. V. Tags: ARTICLES Source Type: research
Absence of alsin function leads to corticospinal motor neuron vulnerability via novel disease mechanisms
Mutations in the ALS2 gene result in early-onset amyotrophic lateral sclerosis, infantile-onset ascending hereditary spastic paraplegia and juvenile primary lateral sclerosis, suggesting prominent upper motor neuron involvement. However, the importance of alsin function for corticospinal motor neuron (CSMN) health and stability remains unknown. To date, four separate alsin knockout (AlsinKO) mouse models have been generated, and despite hopes of mimicking human pathology, none displayed profound motor function defects. This, however, does not rule out the possibility of neuronal defects within CSMN, which is not easy to de...
Source: Human Molecular Genetics - February 23, 2016 Category: Genetics & Stem Cells Authors: Gautam, M., Jara, J. H., Sekerkova, G., Yasvoina, M. V., Martina, M., Özdinler, P. H. Tags: ARTICLES Source Type: research
Wnt4 coordinates directional cell migration and extension of the Müllerian duct essential for ontogenesis of the female reproductive tract
In conclusion, the results suggest that the Wnt4 gene encodes signals that are important for various aspects of female reproductive tract development. (Source: Human Molecular Genetics)
Source: Human Molecular Genetics - February 23, 2016 Category: Genetics & Stem Cells Authors: Prunskaite-Hyyryläinen, R., Skovorodkin, I., Xu, Q., Miinalainen, I., Shan, J., Vainio, S. J. Tags: ARTICLES Source Type: research
AMPK activation protects from neuronal dysfunction and vulnerability across nematode, cellular and mouse models of Huntington's disease
The adenosine monophosphate activated kinase protein (AMPK) is an evolutionary-conserved protein important for cell survival and organismal longevity through the modulation of energy homeostasis. Several studies suggested that AMPK activation may improve energy metabolism and protein clearance in the brains of patients with vascular injury or neurodegenerative disease. However, in Huntington's disease (HD), AMPK may be activated in the striatum of HD mice at a late, post-symptomatic phase of the disease, and high-dose regiments of the AMPK activator 5-aminoimidazole-4-carboxamide ribonucleotide may worsen neuropathological...
Source: Human Molecular Genetics - February 23, 2016 Category: Genetics & Stem Cells Authors: Vazquez-Manrique, R. P., Farina, F., Cambon, K., Dolores Sequedo, M., Parker, A. J., Millan, J. M., Weiss, A., Deglon, N., Neri, C. Tags: ARTICLES Source Type: research
Contents Page
(Source: Human Molecular Genetics)
Source: Human Molecular Genetics - February 23, 2016 Category: Genetics & Stem Cells Tags: FRONT-MATTER/BACK-MATTER Source Type: research
