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Human Molecular Genetics

Takashi Iizuka, Kazusaku Kamiya, Satoru Gotoh, Yoshinobu Sugitani, Masaaki Suzuki, Tetsuo Noda, Osamu Minowa, Katsuhisa Ikeda
No abstract text is available yet for this article.
February 28, 2019: Human Molecular Genetics
Samuel Chiquita, Mário Ribeiro, João Castelhano, Francisco Oliveira, José Sereno, Marta Batista, Antero Abrunhosa, Ana C Rodrigues-Neves, Rafael Carecho, Filipa Baptista, Catarina Gomes, Paula I Moreira, António F Ambrósio, Miguel Castelo-Branco
The understanding of the natural history of Alzheimer's disease (AD) and temporal trajectories of in vivo molecular mechanisms requires longitudinal approaches. A behavioral and multimodal imaging study was performed at 4/8/12 and 16 months of age in a triple transgenic mouse model of AD (3xTg-AD). Behavioral assessment included the open field and novel object recognition tests. Molecular characterization evaluated hippocampal levels of amyloid β (Aβ) and hyperphosphorylated tau. Magnetic resonance imaging (MRI) included assessment of hippocampal structural integrity, blood-brain barrier (BBB) permeability and neurospectroscopy to determine levels of the endogenous neuroprotector taurine...
February 28, 2019: Human Molecular Genetics
H M Chowdhury, N Sharmin, M Yuzbasioglu Baran, L Long, N W Morrell, R C Trembath, Md Talat Nasim
Pulmonary Arterial Hypertension (PAH) is a devastating cardiovascular disorder characterised by the remodelling of pre-capillary pulmonary arteries. The vascular remodelling observed in PAH patients results from excessive proliferation and apoptosis resistance of pulmonary arterial smooth muscle (PASMCs) and endothelial cells (PAECs). We have previously demonstrated that mutations in the type II receptor for bone morphogenetic protein (BMPRII) underlie the majority of the familial and inherited forms of the disease...
February 27, 2019: Human Molecular Genetics
Desiree M Baron, Tyler Matheny, Yen-Chen Lin, John D Leszyk, Kevin Kenna, Katherine V Gall, David P Santos, Maeve Tischbein, Salome Funes, Lawrence J Hayward, Evangelos Kiskinis, John E Landers, Roy Parker, Scott A Shaffer, Daryl A Bosco
Aberrant translational repression is a feature of multiple neurodegenerative diseases. The association between disease-linked proteins and stress granules further implicates impaired stress responses in neurodegeneration. However, our knowledge of the proteins that evade translational repression is incomplete. It is also unclear whether disease-linked proteins influence the proteome under conditions of translational repression. To address these questions, a quantitative proteomics approach was used to identify proteins that evade stress-induced translational repression in arsenite-treated cells expressing either WT or ALS-linked mutant FUS...
February 26, 2019: Human Molecular Genetics
Tatiana M Fontelonga, Brennan Jordan, Andreia M Nunes, Pamela Barraza-Flores, Nicholas Bolden, Ryan D Wuebbles, Lesley Mathews Greiner, Xin Hu, Marc Ferrer, Juan Marugan, Noel Southall, Dean J Burkin
Duchenne muscular dystrophy (DMD) is a lethal, muscle degenerative disease causing premature death of affected children. DMD is characterized by mutations in the dystrophin gene that result in a loss of the dystrophin protein. Loss of dystrophin causes an associated reduction in proteins of the dystrophin glycoprotein complex (DGC), leading to contraction-induced sarcolemmal weakening, muscle tearing, fibrotic infiltration and rounds of degeneration and failed regeneration affecting satellite cell populations...
February 26, 2019: Human Molecular Genetics
Carmela Fusco, Grazia Nardella, Rita Fischetto, Massimiliano Copetti, Antonio Petracca, Francesca Annunziata, Bartolomeo Augello, Maria Cecilia D'Asdia, Simona Petrucci, Teresa Mattina, Annalisa Rella, Matteo Cassina, Mario Bengala, Tommaso Biagini, Francesco Andrea Causio, Camilla Caldarini, Francesco Brancati, Alessandro De Luca, Vito Guarnieri, Lucia Micale, Leonardo D'Agruma, Marco Castori
Hereditary multiple osteochondromas (HMO) is a rare autosomal dominant skeletal disorder, caused by heterozygous variants in either EXT1 or EXT2, which encode proteins involved in the biogenesis of heparan sulphate. Pathogenesis and genotype-phenotype correlations remain poorly understood. We studied 114 HMO families (158 affected individuals) with causative EXT1 or EXT2 variants identified by Sanger sequencing, or MLPA and qPCR. Eighty-seven disease-causative variants (55 novel and 32 known) were identified including frameshift (42%), nonsense (32%), missense (11%), splicing (10%) variants and genomic rearrangements (5%)...
February 26, 2019: Human Molecular Genetics
Tarkowski Bartosz, Kuchcinska Kinga, Blazejczyk Magdalena, Jaworski Jacek
Several mosaic mutations of the mammalian/mechanistic target of rapamycin (mTOR) have recently been found in patients with cortical malformations, such as hemimegalencephaly (HME) and focal cortical dysplasia (FCD). Although all of them should activate mTOR signaling, comparisons of the impact of different mTOR mutations on brain development have been lacking. Also it remains unknown if any potential differences these mutations may have on cortical development are directly related to a degree of mTOR signaling increase...
February 21, 2019: Human Molecular Genetics
Amanda J Kedaigle, Ernest Fraenkel, Ranjit S Atwal, Min Wu, James F Gusella, Marcy E MacDonald, Julia A Kaye, Steven Finkbeiner, Virginia B Mattis, Colton M Tom, Clive Svendsen, Alvin R King, Yumay Chen, Jennifer T Stocksdale, Ryan G Lim, Malcolm Casale, Ping H Wang, Leslie M Thompson, Sergey S Akimov, Tamara Ratovitski, Nicolas Arbez, Christopher A Ross
Altered cellular metabolism is believed to be an important contributor to pathogenesis of the neurodegenerative disorder Huntington's disease (HD). Research has primarily focused on mitochondrial toxicity, which can cause death of the vulnerable striatal neurons, but other aspects of metabolism have also been implicated. Most previous studies have been carried out using post-mortem human brain or non-human cells. Here, we studied bioenergetics in an induced pluripotent stem cell (iPSC)-based model of the disease...
February 15, 2019: Human Molecular Genetics
Fabian Dorninger, Theresa König, Petra Scholze, Michael L Berger, Gerhard Zeitler, Christoph Wiesinger, Anna Gundacker, Daniela D Pollak, Sigismund Huck, Wilhelm W Just, Sonja Forss-Petter, Christian Pifl, Johannes Berger
Plasmalogens, the most prominent ether (phospho)lipids in mammals, are structural components of most cellular membranes. Due to their physicochemical properties and abundance in the central nervous system, a role of plasmalogens in neurotransmission has been proposed, but conclusive data are lacking. Here, we targeted this issue in the glyceronephosphate O-acyltransferase (Gnpat) KO mouse, a model of complete deficiency in ether lipid biosynthesis. Throughout the study, focusing on adult male animals, we found reduced brain levels of various neurotransmitters...
February 13, 2019: Human Molecular Genetics
J Spencer Hauck, Jeovanna Lowe, Neha Rastogi, Kevin E McElhanon, Jennifer M Petrosino, Kyra K Peczkowski, Ashlee N Chadwick, Jonathan G Zins, Federica Accornero, Paul M L Janssen, Noah L Weisleder, Jill A Rafael-Fortney
Mineralocorticoid receptor (MR) drugs have been used clinically for decades to treat cardiovascular diseases. MR antagonists show preclinical efficacy not only for heart in Duchenne muscular dystrophy models, but also improve skeletal muscle force and muscle membrane integrity. The mechanisms of action of MR antagonists in skeletal muscles are entirely unknown. Since MR are present in many cell types in the muscle microenvironment, it is critical to define cell-intrinsic functions in each cell type to ultimately optimize antagonist efficacy for use in the widest variety of diseases...
February 13, 2019: Human Molecular Genetics
Claudia H Huichalaf, Ismael Al-Ramahi, Kyung-Won Park, Stacy D Grunke, Nan Lu, Maria de Haro, Karla El-Zein, Tatiana Gallego-Flores, Alma M Perez, Sung Yun Jung, Juan Botas, Huda Y Zoghbi, Joanna L Jankowsky
An early hallmark of Alzheimer's disease is the accumulation of amyloid-β, inspiring numerous therapeutic strategies targeting this peptide. An alternative approach is to destabilize the amyloid precursor protein (APP) from which Aβ is derived. We interrogated innate pathways governing APP stability using a siRNA screen for modifiers whose own reduction diminished APP in human cell lines and transgenic Drosophila. As proof-of-principle, we validated PKCβ - a known modifier identified by the screen - in an APP transgenic mouse model...
February 12, 2019: Human Molecular Genetics
Federico Zambon, Marta Cherubini, Hugo J R Fernandes, Charmaine Lang, Brent J Ryan, Viola Volpato, Nora Bengoa-Vergniory, Siv Vingill, Moustafa Attar, Heather D E Booth, Walther Haenseler, Jane Vowles, Rory Bowden, Caleb Webber, Sally A Cowley, Richard Wade-Martins
Parkinson's disease (PD) is the second most common neurodegenerative disorder and a central role for α-Synuclein (αSyn; SNCA) in disease aetiology has been proposed based on genetics and neuropathology. To better understand the pathological mechanisms of αSyn, we generated induced pluripotent stem cells (iPSCs) from healthy individuals and PD patients carrying the A53T SNCA mutation or a triplication of the SNCA locus and differentiated them into dopaminergic neurons (DAn). iPSC-derived DAn from PD patients carrying either mutation showed increased intracellular αSyn accumulation, and DAn from patients carrying the SNCA triplication displayed oligomeric αSyn pathology and elevated αSyn extracellular release...
February 11, 2019: Human Molecular Genetics
Davide Randazzo, Umara Khalique, Joseph J Belanto, Aster Kenea, Dana M Talsness, John T Olthoff, Michelle D Tran, Kristien J Zaal, Katherine Pak, Iago Pinal-Fernandez, Andrew L Mammen, Dan Sackett, James M Ervasti, Evelyn Ralston
No abstract text is available yet for this article.
February 11, 2019: Human Molecular Genetics
Frédéric Anglès, Darren M Hutt, William E Balch
Understanding the role of the epigenome in protein misfolding diseases remains a challenge in light of genetic diversity found in the world-wide population revealed by human genome sequencing efforts and the highly variable response of the disease population to therapeutics. An ever-growing body of evidence has shown that histone deacetylase (HDAC) inhibitors (HDACi) can have significant benefit in correcting protein misfolding diseases that occur in response to both familial and somatic mutation. Cystic fibrosis (CF) is a familial autosomal recessive disease, caused by genetic diversity in the CF transmembrane conductance regulator (CFTR) gene, a cAMP-dependent chloride channel expressed at the apical plasma membrane of epithelial cells in multiple tissues...
February 7, 2019: Human Molecular Genetics
Jin Zhou, Benjamin Ng, Nicole S J Ko, Lorna R Fiedler, Ester Khin, Andrea Lim, Norliza E Sahib, Yajun Wu, Sonia P Chothani, Sebastian Schafer, Boon-Huat Bay, Rohit A Sinha, Stuart A Cook, Paul M Yen
Titin-truncating variants (TTNtv) are the most common genetic cause of dilated cardiomyopathy (DCM). TTNtv occur in ~1% of the general population and causes subclinical cardiac remodeling in asymptomatic carriers. In rat models with either proximal or distal TTNtv, we previously showed altered cardiac metabolism at baseline and impaired cardiac function in response to stress. However, the molecular mechanism(s) underlying these effects remains unknown. In the current study, we used rat models of TTNtv to investigate the effect of TTNtv on autophagy and mitochondrial function, which are essential for maintaining cellular metabolic homeostasis and cardiac function...
February 4, 2019: Human Molecular Genetics
Carola Hedberg-Oldfors, Alexandra Abramsson, Daniel P S Osborn, Olof Danielsson, Afsoon Fazlinezhad, Yalda Nilipour, Laila Hübbert, Inger Nennesmo, Kittichate Visuttijai, Jaipreet Bharj, Evmorfia Petropoulou, Azza Shoreim, Barbara Vona, Najmeh Ahangari, Marcela Dávila López, Mohammad Doosti, Rakesh Kumar Banote, Reza Maroofian, Malin Edling, Mehdi Taherpour, Henrik Zetterberg Md, Ehsan Ghayoor Karimiani, Anders Oldfors, Yalda Jamshidi
Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiovascular disorder, yet the genetic cause of up to 50% of cases remains unknown. Here we show that mutations in KLHL24 cause hypertrophic cardiomyopathy in humans. Using genome-wide linkage analysis and exome sequencing we identified homozygous mutations in KLHL24 in two consanguineous families with HCM. Of the eleven young affected adults identified, three died suddenly and one had a cardiac transplant due to heart failure. KLHL24 is a member of the kelch-like protein family, which act as substrate-specific adaptors Cullin E3 ubiquitin ligases...
February 1, 2019: Human Molecular Genetics
Khadija Hajji, Ali Mteyrek, Jun Sun, Marlène Cassar, Sana Mezghani, Jérôme Leprince, David Vaudry, Olfa Masmoudi-Kouki, Serge Birman
Parkinson's disease (PD) is a progressive neurodegenerative movement disorder that can arise after long-term exposure to environmental oxidative stressors, such as the herbicide paraquat (PQ). Here we investigated the potential neuroprotective action of vertebrate pituitary adenylate cyclase-activating polypeptide (PACAP) against PQ in Drosophila. We found that pretreatment with this neuropeptide applied to the ventral nerve cord (VNC) at low doses markedly extended the survival of wild-type decapitated flies exposed to neurotoxic levels of PQ or dopamine (DA)...
January 30, 2019: Human Molecular Genetics
Xueqin Gao, Ying Tang, Sarah Amra, Xuying Sun, Yan Cui, Haizi Cheng, Bing Wang, Johnny Huard
The dystrophin-/-/utrophin-/- double knockout (dKO-Hom) mouse is a murine model of human Duchenne muscular dystrophy (DMD). This study investigated the bone and muscle abnormalities of dKO-Hom mouse and mechanisms. We collected bone and skeletal muscle samples from control mice and three muscular dystrophic mouse models at different ages, and performed MicroCT and histological analyses of both bone and skeletal muscle tissues. Serum RANKL and SOST levels, osteoclastogenesis and serum proteomics were also analyzed...
January 28, 2019: Human Molecular Genetics
Masashi Ikuno, Hodaka Yamakado, Hisako Akiyama, Laxmi Kumar Parajuli, Katsutoshi Taguchi, Junko Hara, Norihito Uemura, Yusuke Hatanaka, Katsumi Higaki, Kousaku Ohno, Masaki Tanaka, Masato Koike, Yoshio Hirabayashi, Ryosuke Takahashi
Parkinson's disease (PD) is characterized by dopaminergic cell loss and the accumulation of pathological alpha synuclein (asyn), but its precise pathomechanism remains unclear, and no appropriate animal model has yet been established. Recent studies have shown that a heterozygous mutation of glucocerebrosidase (gba) is one of the most important genetic risk factors in PD. To create mouse model for PD, we crossed asyn Bacterial Artificial Chromosome transgenic mice with gba heterozygous knockout mice. These double-mutant mice express human asyn in a physiological manner through its native promoter and showed an increase in phosphorylated asyn in the regions vulnerable to PD, such as the olfactory bulb and dorsal motor nucleus of the vagus nerve...
January 28, 2019: Human Molecular Genetics
Ryohei Furumai, Kota Tamada, Xiaoxi Liu, Toru Takumi
UBE3A is a gene responsible for the pathogenesis of Angelman syndrome (AS), a neurodevelopmental disorder characterized by symptoms such as intellectual disability, delayed development and severe speech impairment. UBE3A encodes an E3 ubiquitin ligase, for which several targets have been identified, including synaptic molecules. Although proteolysis mainly occurs in the cytoplasm, UBE3A is localized to the cytoplasm and the nucleus. In fact, UBE3A is also known as a transcriptional regulator of the family of nuclear receptors...
January 26, 2019: Human Molecular Genetics
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