Antisense pre-treatment increases gene therapy efficacy in dystrophic muscles
In preclinical models for Duchenne muscular dystrophy, dystrophin restoration during adeno-associated virus (AAV)-U7-mediated exon-skipping therapy was shown to decrease drastically after six months in treated muscles. This decline in efficacy is strongly correlated with the loss of the therapeutic AAV genomes, probably due to alterations of the dystrophic myofiber membranes. To improve the membrane integrity of the dystrophic myofibers at the time of AAV-U7 injection, mdx muscles were pre-treated with a single dose of the peptide-phosphorodiamidate morpholino (PPMO) antisense oligonucleotides that induced temporary dystro...
Source: Human Molecular Genetics - December 22, 2016 Category: Genetics & Stem Cells Authors: Peccate, C., Mollard, A., Le Hir, M., Julien, L., McClorey, G., Jarmin, S., Le Heron, A., Dickson, G., Benkhelifa-Ziyyat, S., Pietri-Rouxel, F., Wood, M. J., Voit, T., Lorain, S. Tags: ARTICLES Source Type: research
Rescue of neural crest-derived phenotypes in a zebrafish CHARGE model by Sox10 downregulation
We report for the first time, defects in myelinating Schwann cells, enteric neurons and pigment cells in a CHARGE model. We also observe defects in the specification of peripheral neurons and the craniofacial skeleton as previously reported. Chd7 morphants have impaired migration of neural crest cells and deregulation of sox10 expression from the early stages. Knocking down Sox10 in the zebrafish CHARGE model rescued the defects in Schwann cells and craniofacial cartilage. Our zebrafish CHARGE model thus reveals important regulatory roles for Chd7 at multiple points of neural crest development viz., migration, fate choice ...
Source: Human Molecular Genetics - December 22, 2016 Category: Genetics & Stem Cells Authors: Asad, Z., Pandey, A., Babu, A., Sun, Y., Shevade, K., Kapoor, S., Ullah, I., Ranjan, S., Scaria, V., Bajpai, R., Sachidanandan, C. Tags: ARTICLES Source Type: research
Cancer-associated isocitrate dehydrogenase mutations induce mitochondrial DNA instability
A major advance in understanding the progression and prognostic outcome of certain cancers, such as low-grade gliomas, acute myeloid leukaemia, and chondrosarcomas, has been the identification of early-occurring mutations in the NADP+-dependent isocitrate dehydrogenase genes IDH1 and IDH2. These mutations result in the production of the onco-metabolite D-2-hydroxyglutarate (2HG), thought to contribute to disease progression. To better understand the mechanisms of 2HG pathophysiology, we introduced the analogous glioma-associated mutations into the NADP+ isocitrate dehydrogenase genes (IDP1, IDP2, IDP3) in Saccharomyces cer...
Source: Human Molecular Genetics - December 22, 2016 Category: Genetics & Stem Cells Authors: Kingsbury, J. M., Shamaprasad, N., Billmyre, R. B., Heitman, J., Cardenas, M. E. Tags: ARTICLES Source Type: research
LRRK2 modulates microglial activity through regulation of chemokine (C-X3-C) receptor 1 -mediated signalling pathways
In conclusion, our findings reveal a previously unknown regulatory role for LRRK2 in CX3CR1 signalling and suggest that an increase of CX3CR1 activity contributes to the attenuated inflammatory responses in Lrrk2-null microglia. (Source: Human Molecular Genetics)
Source: Human Molecular Genetics - December 22, 2016 Category: Genetics & Stem Cells Authors: Ma, B., Xu, L., Pan, X., Sun, L., Ding, J., Xie, C., Koliatsos, V. E., Cai, H. Tags: ARTICLES Source Type: research
The K153Del PRPH2 mutation differentially impacts photoreceptor structure and function
Peripherin 2 (Prph2) is a photoreceptor tetraspanin, and deletion of codon 153 (K153) leads to retinitis pigmentosa, pattern dystrophy, and fundus flavimaculatus in the same family. To study this variability, we generated a K153-Prph2 knockin mouse. K153-Prph2 cannot form the complexes required for outer segment formation, and in cones cannot interact with its binding partner rod outer segment membrane protein 1. K153 causes dominant defects in rod and cone function; however, rod but not cone ultrastructure is improved by the presence of K153-Prph2. Likewise, supplementation of K153 heterozygotes with WT-Prph2 results in s...
Source: Human Molecular Genetics - December 22, 2016 Category: Genetics & Stem Cells Authors: Chakraborty, D., Conley, S. M., Zulliger, R., Naash, M. I. Tags: ARTICLES Source Type: research
Genetic ablation of IP3 receptor 2 increases cytokines and decreases survival of SOD1G93A mice
Amyotrophic lateral sclerosis (ALS) is a devastating progressive neurodegenerative disease characterized by the selective death of motor neurons. Disease pathophysiology is complex and not yet fully understood. Higher gene expression of the inositol 1,4,5-trisphosphate receptor 2 gene (ITPR2), encoding the IP3 receptor 2 (IP3R2), was detected in sporadic ALS patients. Here, we demonstrate that IP3R2 gene expression was also increased in spinal cords of ALS mice. Moreover, an increase of IP3R2 expression was observed in other models of chronic and acute neurodegeneration. Upregulation of IP3R2 gene expression could be induc...
Source: Human Molecular Genetics - December 22, 2016 Category: Genetics & Stem Cells Authors: Staats, K. A., Humblet-Baron, S., Bento-Abreu, A., Scheveneels, W., Nikolaou, A., Deckers, K., Lemmens, R., Goris, A., Van Ginderachter, J. A., Van Damme, P., Hisatsune, C., Mikoshiba, K., Liston, A., Robberecht, W., Van Den Bosch, L. Tags: ARTICLES Source Type: research
The PINK1, synphilin-1 and SIAH-1 complex constitutes a novel mitophagy pathway
In this study, we showed that synphilin-1 interacted with PINK1 and was recruited to the mitochondria. Once in the mitochondria, it promoted PINK1-dependent mitophagy, as revealed by Atg5 knockdown experiments and the recruitment of LC3 and Lamp1 to the mitochondria. PINK1–synphilin-1 mitophagy did not depend on PINK1-mediated phosphorylation of synphilin-1 and occurred in the absence of parkin. Synphilin-1 itself caused depolarization of the mitochondria and increased the amount of uncleaved PINK1 at the organelle. Furthermore, synphilin-1 recruited seven in absentia homolog (SIAH)-1 to the mitochondria where it pro...
Source: Human Molecular Genetics - December 22, 2016 Category: Genetics & Stem Cells Authors: Szargel, R., Shani, V., Abd Elghani, F., Mekies, L. N., Liani, E., Rott, R., Engelender, S. Tags: ARTICLES Source Type: research
Identification of plexin A4 as a novel clusterin receptor links two Alzheimers disease risk genes
Although abundant genetic and biochemical evidence strongly links Clusterin (CLU) to Alzheimer disease (AD) pathogenesis, the receptor for CLU within the adult brain is currently unknown. Using unbiased approaches, we identified Plexin A4 (PLXNA4) as a novel, high-affinity receptor for CLU in the adult brain. PLXNA4 protein expression was high in brain with much lower levels in peripheral organs. CLU protein levels were significantly elevated in the cerebrospinal fluid (CSF) of Plxna4-/- mice and, in humans, CSF levels of CLU were also associated with PLXNA4 genotype. Human AD brains had significantly increased the levels ...
Source: Human Molecular Genetics - December 22, 2016 Category: Genetics & Stem Cells Authors: Kang, S. S., Kurti, A., Wojtas, A., Baker, K. E., Liu, C.-C., Kanekiyo, T., Deming, Y., Cruchaga, C., Estus, S., Bu, G., Fryer, J. D. Tags: ARTICLES Source Type: research
Transcriptome sequencing reveals aberrant alternative splicing in Huntington's disease
Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder caused by a CAG expansion in the gene-encoding Huntingtin (HTT). Transcriptome dysregulation is a major feature of HD pathogenesis, as revealed by a large body of work on gene expression profiling of tissues from human HD patients and mouse models. These studies were primarily focused on transcriptional changes affecting steady-state overall gene expression levels using microarray based approaches. A major missing component, however, has been the study of transcriptome changes at the post-transcriptional level, such as alternative splicing....
Source: Human Molecular Genetics - December 22, 2016 Category: Genetics & Stem Cells Authors: Lin, L., Park, J. W., Ramachandran, S., Zhang, Y., Tseng, Y.-T., Shen, S., Waldvogel, H. J., Curtis, M. A., Faull, R. L. M., Troncoso, J. C., Pletnikova, O., Ross, C. A., Davidson, B. L., Xing, Y. Tags: ARTICLES Source Type: research
Autophagic lysosome reformation dysfunction in glucocerebrosidase deficient cells: relevance to Parkinson disease
Glucocerebrosidase (GBA1) gene mutations increase the risk of Parkinson disease (PD). While the cellular mechanisms associating GBA1 mutations and PD are unknown, loss of the glucocerebrosidase enzyme (GCase) activity, inhibition of autophagy and increased α-synuclein levels have been implicated. Here we show that autophagy lysosomal reformation (ALR) is compromised in cells lacking functional GCase. ALR is a cellular process controlled by mTOR which regenerates functional lysosomes from autolysosomes formed during macroautophagy. A decrease in phopho-S6K levels, a marker of mTOR activity, was observed in models of G...
Source: Human Molecular Genetics - December 22, 2016 Category: Genetics & Stem Cells Authors: Magalhaes, J., Gegg, M. E., Migdalska-Richards, A., Doherty, M. K., Whitfield, P. D., Schapira, A. H. V. Tags: ARTICLES Source Type: research
Functional rescue of REP1 following treatment with PTC124 and novel derivative PTC-414 in human choroideremia fibroblasts and the nonsense-mediated zebrafish model
Choroideremia (CHM) is an X-linked chorioretinal dystrophy that is caused by mutations within a single gene, CHM. Currently no effective treatment exists for these patients. Since over 30% of patients harbour nonsense mutations in CHM, nonsense suppression therapy using translational readthrough inducing drugs may provide functional rescue of REP1, thus attenuating progressive sight loss. Here, we employed two CHM model systems to systematically test the efficacy and safety of ataluren (PTC124) and its novel analog PTC-414: (1) the chmru848 zebrafish, the only nonsense mutation animal model of CHM harbouring a TAA nonsense...
Source: Human Molecular Genetics - December 22, 2016 Category: Genetics & Stem Cells Authors: Moosajee, M., Tracey-White, D., Smart, M., Weetall, M., Torriano, S., Kalatzis, V., da Cruz, L., Coffey, P., Webster, A. R., Welch, E. Tags: ARTICLES Source Type: research
A novel missense variant in PRKCB segregates low-frequency hearing loss in an autosomal dominant family with Menieres disease
Meniere’s Disease (MD) is a complex disorder associated with an accumulation of endolymph in the membranous labyrinth in the inner ear. It is characterized by recurrent attacks of spontaneous vertigo associated with sensorineural hearing loss (SNHL) and tinnitus. The SNHL usually starts at low and medium frequencies with a variable progression to high frequencies. We identified a novel missense variant in the PRKCB gene in a Spanish family with MD segregating low-to-middle frequency SNHL. Confocal imaging showed strong PKCB II protein labelling in non-sensory cells, the tectal cells and inner border cells of the rat ...
Source: Human Molecular Genetics - December 22, 2016 Category: Genetics & Stem Cells Authors: Martin-Sierra, C., Requena, T., Frejo, L., Price, S. D., Gallego-Martinez, A., Batuecas-Caletrio, A., Santos-Perez, S., Soto-Varela, A., Lysakowski, A., Lopez-Escamez, J. A. Tags: ARTICLES Source Type: research
Motor neuron mitochondrial dysfunction in spinal muscular atrophy
Spinal muscular atrophy (SMA), the leading genetic cause of infant mortality, predominantly affects high metabolic tissues including motor neurons, skeletal muscles and the heart. Although the genetic cause of SMA has been identified, mechanisms underlying tissue-specific vulnerability are not well understood. To study these mechanisms, we carried out a deep sequencing analysis of the transcriptome of spinal motor neurons in an SMA mouse model, in which we unexpectedly found changes in many genes associated with mitochondrial bioenergetics. Importantly, functional measurement of mitochondrial activities showed decreased ba...
Source: Human Molecular Genetics - December 22, 2016 Category: Genetics & Stem Cells Authors: Miller, N., Shi, H., Zelikovich, A. S., Ma, Y.-C. Tags: ARTICLES Source Type: research
Table of Contents
(Source: Human Molecular Genetics)
Source: Human Molecular Genetics - December 22, 2016 Category: Genetics & Stem Cells Tags: Cover / Standing Material Source Type: research
Subscriptions Page
(Source: Human Molecular Genetics)
Source: Human Molecular Genetics - December 22, 2016 Category: Genetics & Stem Cells Tags: Cover / Standing Material Source Type: research
