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Human Molecular Genetics

Nadège Vernet, Shantha K Mahadevaiah, Dirk G de Rooij, Paul S Burgoyne, Peter J I Ellis
During spermatogenesis, germ cells that fail to synapse their chromosomes or fail to undergo meiotic sex chromosome inactivation (MSCI) are eliminated via apoptosis during mid-pachytene. Previous work showed that Y-linked genes Zfy1 and Zfy2 act as "executioners" for this checkpoint, and that wrongful expression of either gene during pachytene triggers germ cell death. Here, we show that in mice, Zfy genes are also necessary for efficient MSCI and the sex chromosomes are not correctly silenced in Zfy-deficient spermatocytes...
October 13, 2016: Human Molecular Genetics
Nelly Redolfi, Luisa Galla, Andrea Maset, Luca Murru, Eleonora Savoia, Ilaria Zamparo, Angela Gritti, Pierre Billuart, Maria Passafaro, Claudia Lodovichi
Among the X-linked genes associated to intellectual disability, Oligophrenin-1 (OPHN1) encodes for a Rho GTPase-activating protein, a key regulator of several developmental processes, such as dendrite and spine formation and synaptic activity. Inhibitory interneurons play a key role in the development and function of neuronal circuits. Whether mutation of OPHN1 can affect morphology and synaptic properties of inhibitory interneurons remains poorly understood. To address these open questions, we studied in a well established mouse model of X-linked intellectual disability, i...
October 13, 2016: Human Molecular Genetics
Piero Pingitore, Paola Dongiovanni, Benedetta Maria Motta, Marica Meroni, Saverio Massimo Lepore, Rosellina Margherita Mancina, Serena Pelusi, Cristina Russo, Andrea Caddeo, Giorgio Rossi, Tiziana Montalcini, Arturo Pujia, Olov Wiklund, Luca Valenti, Stefano Romeo
Liver fibrosis is a pathological scarring response to chronic hepatocellular injury and hepatic stellate cells (HSCs) are key players in this process. PNPLA3 I148M is a common variant robustly associated with liver fibrosis but the mechanisms underlying this association are unknown.We aimed to examine a) the effect of fibrogenic and proliferative stimuli on PNPLA3 levels in HSCs and b) the role of wild type and mutant PNPLA3 overexpression on markers of HSC activation and fibrosis.Here we show that PNPLA3 is upregulated by the fibrogenic cytokine transforming growth factor-beta (TGF-β), but not by platelet-derived growth factor (PDGF), and is involved in the TGF-β-induced reduction in lipid droplets in primary human HSCs...
October 13, 2016: Human Molecular Genetics
Tereza Vaclová, Nicholas T Woods, Diego Megías, Sergio Gomez-Lopez, Fernando Setién, José María García Bueno, José Antonio Macías, Alicia Barroso, Miguel Urioste, Manel Esteller, Alvaro N A Monteiro, Javier Benítez, Ana Osorio
BRCA1-deficient cells show defects in DNA repair and rely on other members of the DNA repair machinery, which makes them sensitive to PARP inhibitors (PARPi). Although carrying a germline pathogenic variant in BRCA1/2 is the best determinant of response to PARPi, a significant percentage of the patients do not show sensitivity and/or display increased toxicity to the agent. Considering previously suggested mutation-specific BRCA1 haploinsufficiency, we aimed to investigate whether there are any differences in cellular response to PARPi Olaparib depending on the BRCA1 mutation type...
October 13, 2016: Human Molecular Genetics
Clara Sze-Man Tang, Hongsheng Gui, Ashish Kapoor, Jeong-Hyun Kim, Berta Luzón-Toro, Anna Pelet, Grzegorz Burzynski, Francesca Lantieri, Man-Ting So, Courtney Berrios, Hyoung Doo Shin, Raquel M Fernández, Thuy-Linh Le, Joke B G M Verheij, Ivana Matera, Stacey S Cherny, Priyanka Nandakumar, Hyun Sub Cheong, Guillermo Antiñolo, Jeanne Amiel, Jeong-Meen Seo, Dae-Yeon Kim, Jung-Tak Oh, Stanislas Lyonnet, Salud Borrego, Isabella Ceccherini, Robert M W Hofstra, Aravinda Chakravarti, Hyun-Young Kim, Pak Chung Sham, Paul K H Tam, Maria-Mercè Garcia-Barceló
Hirschsprung disease (HSCR) is the most common cause of neonatal intestinal obstruction. It is characterized by the absence of ganglia in the nerve plexuses of the lower gastrointestinal tract. So far, three common disease-susceptibility variants at the RET, SEMA3 and NRG1 loci have been detected through genome-wide association studies (GWAS) in Europeans and Asians to understand its genetic etiologies. Here we present a trans-ethnic meta-analysis of 507 HSCR cases and 1191 controls, combining all published GWAS results on HSCR to fine-map these loci and narrow down the putatively causal variants to 99% credible sets...
October 3, 2016: Human Molecular Genetics
Marilyn C Cornelis, Tim Kacprowski, Cristina Menni, Stefan Gustafsson, Edward Pivin, Jerzy Adamski, Anna Artati, Chin B Eap, Georg Ehret, Nele Friedrich, Andrea Ganna, Idris Guessous, Georg Homuth, Lars Lind, Patrik K Magnusson, Massimo Mangino, Nancy L Pedersen, Maik Pietzner, Karsten Suhre, Henry Völzke, Murielle Bochud, Tim D Spector, Hans J Grabe, Erik Ingelsson
Caffeine is the most widely consumed psychoactive substance in the world and presents with wide interindividual variation in metabolism. This variation may modify potential adverse or beneficial effects of caffeine on health. We conducted a genome-wide association study (GWAS) of plasma caffeine, paraxanthine, theophylline, theobromine and paraxanthine/caffeine ratio among up to 9,876 individuals of European ancestry from six population-based studies. A single SNP at 6p23 (near CD83) and several SNPs at 7p21 (near AHR), 15q24 (near CYP1A2) and 19q13...
October 3, 2016: Human Molecular Genetics
Yukihide Momozawa, Masato Akiyama, Yoichiro Kamatani, Satoshi Arakawa, Miho Yasuda, Shigeo Yoshida, Yuji Oshima, Ryusaburo Mori, Koji Tanaka, Keisuke Mori, Satoshi Inoue, Hiroko Terasaki, Tetsuhiro Yasuma, Shigeru Honda, Akiko Miki, Maiko Inoue, Kimihiko Fujisawa, Kanji Takahashi, Tsutomu Yasukawa, Yasuo Yanagi, Kazuaki Kadonosono, Koh-Hei Sonoda, Tatsuro Ishibashi, Atsushi Takahashi, Michiaki Kubo
AMD is a major cause of blindness in the elderly. Previous sequencing studies of AMD susceptibility genes have revealed the association of rare coding variants in CFH, CFI, C3 and C9 in European population; however, the impact of rare or low-frequency coding variants on AMD susceptibility in other populations is largely unknown. To identify the role of low-frequency coding variants on exudative AMD susceptibility in a Japanese population, we analyzed the association of coding variants of 34 AMD candidate genes in the two-stage design by a multiplex PCR-based target sequencing method...
October 3, 2016: Human Molecular Genetics
Maria Manczak, Ramesh Kandimalla, David Fry, Hiromi Sesaki, P Hemachandra Reddy
The purpose of our study was to understand the protective effects of reduced expression of dynamin-related protein (Drp1) against amyloid beta (Aβ) induced mitochondrial and synaptic toxicities in Alzheimer's disease (AD) progression and pathogenesis. Our recent molecular and biochemical studies revealed that impaired mitochondrial dynamics - increased mitochondrial fragmentation and decreased fusion - in neurons from autopsy brains of AD patients and from transgenic AD mice and neurons expressing Aβ, suggesting that Aβ causes mitochondrial fragmentation in AD...
September 27, 2016: Human Molecular Genetics
Chi Huu Nguyen, Stefan Brenner, Nicole Huttary, Atanas Georgiev Atanasov, Verena Maria Dirsch, Waranya Chatuphonprasert, Sivio Holzner, Serena Stadler, Juliane Riha, Sigurd Krieger, Rainer de Martin, Zsuzsanna Bago-Horvath, Georg Krupitza, Walter Jäger
A causal link between overexpression of aryl hydrocarbon receptor (AHR) and its target cytochrome P450 1A1 (CYP1A1) and metastatic outgrowth of various cancer entities has been established. Nevertheless, the mechanism how AHR/CYP1A1 support metastasis formation is still little understood. In vitro we discovered a potential mechanism facilitating tumour dissemination based on the production of 12(S)-hydroxyeicosatetraenoic acid (12(S)-HETE). Utilising a three-dimensional lymph endothelial cell (LEC) monolayer & MDA-MB231 breast cancer cell spheroid co-culture model in combination with knock-down approach allowed elucidation of the molecular/biochemical basis of AHR/CYP1A1-induced tumour breaching through the LEC barrier...
September 27, 2016: Human Molecular Genetics
Douglas Brubaker, Yu Liu, Junye Wang, Huijing Tan, Ge Zhang, Bo Jacobsson, Louis Muglia, Sam Mesiano, Mark R Chance
Maternal genome influences associate with up to 40% of spontaneous preterm births (PTB). Multiple genome wide association studies (GWAS) have been completed to identify genetic variants associated with PTB. Disappointingly, no highly significant SNPs have replicated in independent cohorts so far. We developed an approach combining protein-protein interaction (PPI) network data with tissue specific gene expression data to "find" SNPs of modest significance to identify candidate genes of functional importance that would otherwise be overlooked...
September 23, 2016: Human Molecular Genetics
Stefanie Atsem, Juliane Reichenbach, Ramya Potabattula, Marcus Dittrich, Caroline Nava, Christel Depienne, Lena Böhm, Simone Rost, Thomas Hahn, Martin Schorsch, Thomas Haaf, Nady El Hajj
Children of older fathers carry an increased risk for developing autism and other disorders. To elucidate the underlying mechanisms, we investigated the correlation of sperm DNA methylation with paternal age and its impact on the epigenome of the offspring. Methylation levels of 9 candidate genes and LINE-1 repeats were quantified by bisulfite pyrosequencing in sperm of 162 donors and 191 cord blood of resulting children (conceived by IVF/ICSI with the same sperm samples). Four genes showed a significant negative correlation between sperm methylation and paternal age...
September 23, 2016: Human Molecular Genetics
Ni-Chung Lee, Yu-May Lee, Pin-Wen Chen, Barry J Byrne, Wuh-Liang Hwu
Aromatic L-amino acid decarboxylase (AADC) deficiency is an inborn error of monoamine neurotransmitter synthesis, which results in dopamine, serotonin, epinephrine, and norepinephrine deficiencies. The DDC gene founder mutation IVS6+4A>T is highly prevalent in Chinese patients with AADC deficiency. In this study, we designed several U1 snRNA vectors to adapt U1 snRNA binding sequences of the mutated DDC gene. We found that only the modified U1 snRNA (IVS-AAA) that completely matched both the intronic and exonic U1 binding sequences of the mutated DDC gene could correct splicing errors of either the mutated human DDC minigene or the mouse artificial splicing construct in vitro We further injected an adeno-associated viral (AAV) vector to express IVS-AAA in the brain of a knock-in mouse model...
September 21, 2016: Human Molecular Genetics
Joseph E Powell, Jenny N Fung, Konstantin Shakhbazov, Yadav Sapkota, Nicole Cloonan, Gibran Hemani, Kristine M Hillman, Susanne Kaufmann, Hien T Luong, Lisa Bowdler, Jodie N Painter, Sarah J Holdsworth-Carson, Peter M Visscher, Marcel E Dinger, Martin Healey, Dale R Nyholt, Juliet D French, Stacey L Edwards, Peter A W Rogers, Grant W Montgomery
Genome-wide association studies (GWAS) have identified markers within the WNT4 region on chromosome 1p36.12 showing consistent and strong association with increasing endometriosis risk. Fine mapping using sequence and imputed genotype data has revealed strong candidates for the causal SNPs within these critical regions; however, the molecular pathogenesis of these SNPs is currently unknown. We used gene expression data collected from whole blood from 862 individuals and endometrial tissue from 136 individuals from independent populations of European descent to examine the mechanism underlying endometriosis susceptibility...
September 20, 2016: Human Molecular Genetics
Benjamin Liou, Yanyan Peng, Ronghua Li, Venette Inskeep, Wujuan Zhang, Brian Quinn, Nupur Dasgupta, Rachel Blackwood, Kenneth D R Setchell, Sheila Fleming, Gregory A Grabowski, John Marshall, Ying Sun
Neuronopathic Gaucher disease (nGD) manifests as severe neurological symptoms in patients with no effective treatment available. Ryanodine receptors (Ryrs) are a family of calcium release channels on intracellular stores. The goal of this study is to determine if Ryrs are potential targets for nGD treatment. A nGD cell model (CBE-N2a) was created by inhibiting acid β-glucosidase (GCase) in N2a cells with conduritol B epoxide (CBE). Enhanced cytosolic calcium in CBE-N2a cells was blocked by either ryanodine or dantrolene, antagonists of Ryrs, and by Genz-161, a glucosylceramide synthase inhibitor, suggesting substrate-mediated ER-calcium efflux occurs through ryanodine receptors...
September 20, 2016: Human Molecular Genetics
Miranda M Darby, Jeffrey T Leek, Ben Langmead, Robert H Yolken, Sarven Sabunciyan
We performed a thorough characterization of expressed Repetitive Element Loci (RE) in the human orbitofrontal cortex (OFC) using directional RNA sequencing data. Considering only sequencing reads that map uniquely onto the human genome, we discovered that the overwhelming majority of intronic and exonic RE are expressed in the same orientation as the gene in which they reside. Our mapping approach enabled the identification of novel differentially expressed RE transcripts between the OFC and peripheral blood lymphocytes...
September 20, 2016: Human Molecular Genetics
Xiaoyi Gao, Drew R Nannini, Kristen Corrao, Mina Torres, Yii-Der I Chen, Bao J Fan, Janey L Wiggs, Kent D Taylor, W James Gauderman, Jerome I Rotter, Rohit Varma
The cornea is the outermost layer of the eye and is a vital component of focusing incoming light on the retina. Central corneal thickness (CCT) is now recognized to have a significant role in ocular health and is a risk factor for various ocular diseases, such as keratoconus and primary open angle glaucoma. Most previous genetic studies utilized European and Asian subjects to identify genetic loci associated with CCT. Minority populations, such as Latinos, may aid in identifying additional loci and improve our understanding of the genetic architecture of CCT...
September 20, 2016: Human Molecular Genetics
Ence Yang, Gang Wang, Jizhou Yang, Beiyan Zhou, Yanan Tian, James J Cai
Increasing evidence shows that, like phenotypic mean, phenotypic variance is also genetically determined, but the underlying mechanisms of genetic control over the variance remain obscure. Here, we conducted variance-association mapping analyses to identify expression variability QTLs (evQTLs), i.e., genomic loci associated with gene expression variance, in humans. We discovered that common genetic variations may contribute to increasing gene expression variability via two distinct modes of action-epistasis and destabilization...
September 20, 2016: Human Molecular Genetics
Shyam Ramachandran, Stephanie L Coffin, Tin-Yun Tang, Chintan D Jobaliya, Ryan M Spengler, Beverly L Davidson
Substantial variability exists in the presentation of complex neurological disorders, and the study of single nucleotide polymorphisms (SNPs) has shed light on disease mechanisms and pathophysiological variability in some cases. However, the vast majority of disease-linked SNPs have unidentified pathophysiological relevance. Here, we tested the hypothesis that SNPs within the miRNA recognition element (MRE; the region of the target transcript to which the miRNA binds) can impart changes in the expression of those genes, either by enhancing or reducing transcript and protein levels...
September 16, 2016: Human Molecular Genetics
Joseph J Belanto, John T Olthoff, Tara L Mader, Christopher M Chamberlain, D'anna M Nelson, Preston M McCourt, Dana M Talsness, Gregg G Gunderson, Dawn A Lowe, James M Ervasti
Absence of the protein dystrophin causes Duchenne muscular dystrophy. Dystrophin directly binds to microtubules in vitro, and its absence in vivo correlates with disorganization of the subsarcolemmal microtubule lattice, increased detyrosination of α-tubulin, and altered redox signaling. We previously demonstrated that the dystrophin homologue utrophin neither binds microtubules in vitro nor rescues microtubule lattice organization when overexpressed in muscles of dystrophin-deficient mdx mice. Here, we fine-mapped the dystrophin domain necessary for microtubule binding to spectrin-like repeats 20-22...
September 16, 2016: Human Molecular Genetics
Danielle A Simmons, Nadia P Belichenko, Ellen C Ford, Sarah Semaan, Marie Monbureau, Sruti Aiyaswamy, Cameron M Holman, Christina Condon, Mehrdad Shamloo, Stephen M Massa, Frank M Longo
Decreases in the ratio of neurotrophic versus neurodegenerative signaling play a critical role in Huntington's disease (HD) pathogenesis and recent evidence suggests that the p75 neurotrophin receptor (NTR) contributes significantly to disease progression. p75(NTR) signaling intermediates substantially overlap with those promoting neuronal survival and synapse integrity and with those affected by the mutant huntingtin (muHtt) protein. MuHtt increases p75(NTR)-associated deleterious signaling and decreases survival signaling suggesting that p75(NTR) could be a valuable therapeutic target...
September 16, 2016: Human Molecular Genetics
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