An enhanced Q175 knock-in mouse model of Huntington disease with higher mutant huntingtin levels and accelerated disease phenotypes
Huntington disease (HD) model mice with heterozygous knock-in (KI) of an expanded CAG tract in exon 1 of the mouse huntingtin (Htt) gene homolog genetically recapitulate the mutation that causes HD, and might be favoured for preclinical studies. However, historically these mice have failed to phenotypically recapitulate the human disease. Thus, homozygous KI mice, which lack wildtype Htt, and are much less relevant to human HD, have been used. The zQ175 model was the first KI mouse to exhibit significant HD-like phenotypes when heterozygous. In an effort to exacerbate HD-like phenotypes and enhance preclinical utility, we ...
Source: Human Molecular Genetics - January 3, 2017 Category: Genetics & Stem Cells Authors: Southwell, A. L., Smith-Dijak, A., Kay, C., Sepers, M., Villanueva, E. B., Parsons, M. P., Xie, Y., Anderson, L., Felczak, B., Waltl, S., Ko, S., Cheung, D., Dal Cengio, L., Slama, R., Petoukhov, E., Raymond, L. A., Hayden, M. R. Tags: ARTICLES Source Type: research
Dystrophin contains multiple independent membrane-binding domains
Dystrophin is a large sub-sarcolemmal protein. Its absence leads to Duchenne muscular dystrophy (DMD). Binding to the sarcolemma is essential for dystrophin to protect muscle from contraction-induced injury. It has long been thought that membrane binding of dystrophin depends on its cysteine-rich (CR) domain. Here, we provide in vivo evidence suggesting that dystrophin contains three additional membrane-binding domains including spectrin-like repeats (R)1-3, R10-12 and C-terminus (CT). To systematically study dystrophin membrane binding, we split full-length dystrophin into ten fragments and examined subcellular localizati...
Source: Human Molecular Genetics - January 3, 2017 Category: Genetics & Stem Cells Authors: Zhao, J., Kodippili, K., Yue, Y., Hakim, C. H., Wasala, L., Pan, X., Zhang, K., Yang, N. N., Duan, D., Lai, Y. Tags: ARTICLES Source Type: research
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(Source: Human Molecular Genetics)
Source: Human Molecular Genetics - January 3, 2017 Category: Genetics & Stem Cells Tags: Cover / Standing Material Source Type: research
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Source: Human Molecular Genetics - January 3, 2017 Category: Genetics & Stem Cells Tags: Cover / Standing Material Source Type: research
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(Source: Human Molecular Genetics)
Source: Human Molecular Genetics - January 3, 2017 Category: Genetics & Stem Cells Tags: Cover / Standing Material Source Type: research
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(Source: Human Molecular Genetics)
Source: Human Molecular Genetics - January 3, 2017 Category: Genetics & Stem Cells Tags: Cover / Standing Material Source Type: research
Intergenic GWAS SNPs are key components of the spatial and regulatory network for human growth
Meta-analysis of genome-wide association studies has resulted in the identification of hundreds of genetic variants associated with growth and stature. Determining how these genetic variants influence growth is important, but most are non-coding, and there is little understanding of how these variants contribute to adult height. To determine the mechanisms by which human variation contributes to growth, we combined spatial genomic connectivity (high-throughput conformation capture) with functional (gene expression, expression Quantitative Trait Loci) data to determine how non-genic loci associated with infant length, puber...
Source: Human Molecular Genetics - December 22, 2016 Category: Genetics & Stem Cells Authors: Schierding, W., Antony, J., Cutfield, W. S., Horsfield, J. A., OSullivan, J. M. Tags: ASSOCIATION STUDIES ARTICLES Source Type: research
A transgenic mouse expressing CHMP2Bintron5 mutant in neurons develops histological and behavioural features of amyotrophic lateral sclerosis and frontotemporal dementia
Mutations in the charged multivesicular body protein 2B (CHMP2B) are associated with frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS), and with a mixed ALS–FTD syndrome. To model this syndrome, we generated a transgenic mouse line expressing the human CHMP2Bintron5 mutant in a neuron-specific manner. These mice developed a dose-dependent disease phenotype. A longitudinal study revealed progressive gait abnormalities, reduced muscle strength and decreased motor coordination. CHMP2Bintron5 mice died due to generalized paralysis. When paralyzed, signs of denervation were present as attested by altered ...
Source: Human Molecular Genetics - December 22, 2016 Category: Genetics & Stem Cells Authors: Vernay, A., Therreau, L., Blot, B., Risson, V., Dirrig-Grosch, S., Waegaert, R., Lequeu, T., Sellal, F., Schaeffer, L., Sadoul, R., Loeffler, J.-P., Rene, F. Tags: ARTICLES Source Type: research
Functional links between SQSTM1 and ALS2 in the pathogenesis of ALS: cumulative impact on the protection against mutant SOD1-mediated motor dysfunction in mice
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by a selective loss of motor neurons in the brain and spinal cord. Multiple toxicity pathways, such as oxidative stress, misfolded protein accumulation, and dysfunctional autophagy, are implicated in the pathogenesis of ALS. However, the molecular basis of the interplay between such multiple factors in vivo remains unclear. Here, we report that two independent ALS-linked autophagy-associated gene products; SQSTM1/p62 and ALS2/alsin, but not antioxidant-related factor; NFE2L2/Nrf2, are implicated in the pathogenesis in mutant SOD1 transg...
Source: Human Molecular Genetics - December 22, 2016 Category: Genetics & Stem Cells Authors: Hadano, S., Mitsui, S., Pan, L., Otomo, A., Kubo, M., Sato, K., Ono, S., Onodera, W., Abe, K., Chen, X., Koike, M., Uchiyama, Y., Aoki, M., Warabi, E., Yamamoto, M., Ishii, T., Yanagawa, T., Shang, H.-F., Yoshii, F. Tags: ARTICLES Source Type: research
MeCP2 deficiency results in robust Rett-like behavioural and motor deficits in male and female rats
Since the identification of MECP2 as the causative gene in the majority of Rett Syndrome (RTT) cases, transgenic mouse models have played a critical role in our understanding of this disease. The use of additional mammalian RTT models offers the promise of further elucidating critical early mechanisms of disease as well as providing new avenues for translational studies. We have identified significant abnormalities in growth as well as motor and behavioural function in a novel zinc-finger nuclease model of RTT utilizing both male and female rats throughout development. Male rats lacking MeCP2 (Mecp2ZFN/y) were noticeably s...
Source: Human Molecular Genetics - December 22, 2016 Category: Genetics & Stem Cells Authors: Patterson, K. C., Hawkins, V. E., Arps, K. M., Mulkey, D. K., Olsen, M. L. Tags: ARTICLES Source Type: research
Loss of MeCP2 in the rat models regression, impaired sociability and transcriptional deficits of Rett syndrome
Mouse models of the transcriptional modulator Methyl-CpG-Binding Protein 2 (MeCP2) have advanced our understanding of Rett syndrome (RTT). RTT is a ‘prototypical’ neurodevelopmental disorder with many clinical features overlapping with other intellectual and developmental disabilities (IDD). Therapeutic interventions for RTT may therefore have broader applications. However, the reliance on the laboratory mouse to identify viable therapies for the human condition may present challenges in translating findings from the bench to the clinic. In addition, the need to identify outcome measures in well-chosen animal m...
Source: Human Molecular Genetics - December 22, 2016 Category: Genetics & Stem Cells Authors: Veeraragavan, S., Wan, Y.-W., Connolly, D. R., Hamilton, S. M., Ward, C. S., Soriano, S., Pitcher, M. R., McGraw, C. M., Huang, S. G., Green, J. R., Yuva, L. A., Liang, A. J., Neul, J. L., Yasui, D. H., LaSalle, J. M., Liu, Z., Paylor, R., Samaco, R. C. Tags: ARTICLES Source Type: research
FANCD2 limits BLM-dependent telomere instability in the alternative lengthening of telomeres pathway
Fanconi anemia and Bloom syndrome are genomic instability syndromes caused by mutations in proteins that participate in overlapping DNA repair and replication pathways. Here, we show that the monoubiquitinated form of the Fanconi Anemia protein FANCD2 acts in opposition to the BLM DNA helicase to restrain telomere replication and recombination in human cells that utilize the Alternative Lengthening of Telomeres (ALT) pathway. ALT relies on exchanges of telomeric DNA to maintain telomeres, a process that we show FANCD2 suppresses. Depletion of FANCD2 results in a hyper-ALT phenotype, including an increase in extrachromosoma...
Source: Human Molecular Genetics - December 22, 2016 Category: Genetics & Stem Cells Authors: Root, H., Larsen, A., Komosa, M., Al-Azri, F., Li, R., Bazett-Jones, D. P., Stephen Meyn, M. Tags: ARTICLES Source Type: research
Improved imputation accuracy in Hispanic/Latino populations with larger and more diverse reference panels: applications in the Hispanic Community Health Study/Study of Latinos (HCHS/SOL)
Imputation is commonly used in genome-wide association studies to expand the set of genetic variants available for analysis. Larger and more diverse reference panels, such as the final Phase 3 of the 1000 Genomes Project, hold promise for improving imputation accuracy in genetically diverse populations such as Hispanics/Latinos in the USA. Here, we sought to empirically evaluate imputation accuracy when imputing to a 1000 Genomes Phase 3 versus a Phase 1 reference, using participants from the Hispanic Community Health Study/Study of Latinos. Our assessments included calculating the correlation between imputed and observed ...
Source: Human Molecular Genetics - December 22, 2016 Category: Genetics & Stem Cells Authors: Nelson, S. C., Stilp, A. M., Papanicolaou, G. J., Taylor, K. D., Rotter, J. I., Thornton, T. A., Laurie, C. C. Tags: ARTICLES Source Type: research
A reduction in Drp1-mediated fission compromises mitochondrial health in autosomal recessive spastic ataxia of Charlevoix Saguenay
The neurodegenerative disease autosomal recessive spastic ataxia of Charlevoix Saguenay (ARSACS) is caused by loss of function of sacsin, a modular protein that is required for normal mitochondrial network organization. To further understand cellular consequences of loss of sacsin, we performed microarray analyses in sacsin knockdown cells and ARSACS patient fibroblasts. This identified altered transcript levels for oxidative phosphorylation and oxidative stress genes. These changes in mitochondrial gene networks were validated by quantitative reverse transcription PCR. Functional impairment of oxidative phosphorylation wa...
Source: Human Molecular Genetics - December 22, 2016 Category: Genetics & Stem Cells Authors: Bradshaw, T. Y., Romano, L. E. L., Duncan, E. J., Nethisinghe, S., Abeti, R., Michael, G. J., Giunti, P., Vermeer, S., Chapple, J. P. Tags: ARTICLES Source Type: research
Cyclooxygenase-2 deficiency impairs muscle-derived stem cell-mediated bone regeneration via cellular autonomous and non-autonomous mechanisms
This study investigated the role of cyclooxygenase-2 (COX-2) expression by donor and host cells in muscle-derived stem cell (MDSC)-mediated bone regeneration utilizing a critical size calvarial defect model. We found that BMP4/green fluorescent protein (GFP)-transduced MDSCs formed significantly less bone in COX-2 knock-out (Cox-2KO) than in COX-2 wild-type (WT) mice. BMP4/GFP-transduced Cox-2KO MDSCs also formed significantly less bone than transduced WT MDSCs when transplanted into calvarial defects created in CD-1 nude mice. The impaired bone regeneration in the Cox-2KO MDSCBMP4/GFP group is associated with downregulati...
Source: Human Molecular Genetics - December 22, 2016 Category: Genetics & Stem Cells Authors: Gao, X., Usas, A., Lu, A., Kozemchak, A., Tang, Y., Poddar, M., Sun, X., Cummins, J. H., Huard, J. Tags: ARTICLES Source Type: research
