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Human Molecular Genetics

Emanuele Barca, Rebecca D Ganetzky, Prasanth Potluri, Marti Juanola-Falgarona, Xiaowu Gai, Dong Li, Chaim Jalas, Yoel Hirsch, Valentina Emmanuele, Saba Tadesse, Marcello Ziosi, Hasan O Akman, Wendy K Chung, Kurenai Tanji, Elizabeth McCormick, Emily Place, Mark Consugar, Eric A Pierce, Hakon Hakonarson, Douglas C Wallace, Michio Hirano, Marni J Falk
Leigh syndrome is a frequent, heterogeneous pediatric presentation of mitochondrial oxidative phosphorylation (OXPHOS) disease, manifesting with psychomotor retardation and necrotizing lesions in brain deep gray matter. OXPHOS occurs at the inner mitochondrial membrane through the integrated activity of 5 protein complexes, of which complex V (CV) functions in a dimeric form to directly generate adenosine triphosphate (ATP). Mutations in several different structural CV subunits cause Leigh syndrome; however, dimerization defects have not been associated with human disease...
June 18, 2018: Human Molecular Genetics
Laura Pellegrini, David N Hauser, Yan Li, Adamantios Mamais, Alexandra Beilina, Ravindran Kumaran, Andrea Wetzel, George Heaton, Iakov Rudenko, Mor Alkaslasi, Natalie Ivanina, Heather L Melrose, Mark R Cookson, Kirsten Harvey
Mutations in leucine-rich repeat kinase 2 (LRRK2) segregate with familial Parkinson's disease (PD) and genetic variation around LRRK2 contributes to risk of sporadic disease. Although knockout of LRRK2 or knock-in of pathogenic mutations into the mouse germline does not result in a PD phenotype, several defects have been reported in the kidneys of LRRK2 knockout mice. To understand LRRK2 function in vivo, we used an unbiased approach to determine which protein pathways are affected in LRRK2 knockout kidneys...
June 18, 2018: Human Molecular Genetics
Dong Li, Tara L Wenger, Christoph Seiler, Michael E March, Alvaro Gutierrez-Uzquiza, Charlly Kao, Elizabeth Bhoj, Lifeng Tian, Misha Rosenbach, Yichuan Liu, Nora Robinson, Mechenzie Behr, Rosetta Chiavacci, Cuiping Hou, Tiancheng Wang, Marina Bakay, Renata Pellegrino da Silva, Jonathan A Perkins, Patrick Sleiman, Michael A Levine, Patricia J Hicks, Maxim Itkin, Yoav Dori, Hakon Hakonarson
Central conducting lymphatic anomaly (CCLA) is one of the complex lymphatic anomalies characterized by dilated lymphatic channels, lymphatic channel dysmotility, and distal obstruction affecting lymphatic drainage. We performed whole exome sequencing (WES) of DNA from a four-generation pedigree and examined the consequences of the variant by transfection of mammalian cells and morpholino and rescue studies in zebrafish. WES revealed a heterozygous mutation in EPHB4 (RefSeq NM_004444.4; c.2334 + 1G>C) and RNA-Seq demonstrated that the EPHB4 mutation destroys the normal donor site, which leads to the use of a cryptic splice donor that results in retention of the intervening 12-bp intron sequence...
June 14, 2018: Human Molecular Genetics
Hanzhang Xia, Fay M Jahr, Nak-Kyeong Kim, Linying Xie, Andrey A Shabalin, Julien Bryois, Douglas H Sweet, Mohamad M Kronfol, Preetha Palasuberniam, MaryPeace McRae, Brien P Riley, Patrick F Sullivan, Edwin J van den Oord, Joseph L McClay
The transcription factor 4 (TCF4) locus is a robust association finding with schizophrenia (SCZ), but little is known about the genes regulated by the encoded transcription factor. Therefore, we conducted chromatin immunoprecipitation sequencing (ChIP-seq) of TCF4 in neural-derived (SH-SY5Y) cells to identify genome-wide TCF4 binding sites, followed by data integration with SCZ association findings. We identified 11,322 TCF4 binding sites overlapping in two ChIP-seq experiments. These sites are significantly enriched for the TCF4 Ebox binding motif (>85% having ≥1 Ebox) and implicate a gene set enriched for genes down-regulated in TCF4 siRNA knockdown experiments, indicating the validity of our findings...
June 14, 2018: Human Molecular Genetics
Yasmin Issop, Denisa Hathazi, Muzamil Majid Khan, Rüdiger Rudolf, Joachim Weis, Sally Spendiff, Clarke R Slater, Andreas Roos, Hanns Lochmüller
Glutamine-fructose-6-phosphate transaminase 1 (GFPT1) is the rate-limiting enzyme in the hexosamine biosynthetic pathway which yields precursors required for protein and lipid glycosylation. Mutations in GFPT1 and other genes downstream of this pathway cause congenital myasthenic syndrome (CMS) characterised by fatigable muscle weakness due to impaired neurotransmission. The precise pathomechanisms at the neuromuscular junction (NMJ) due to a deficiency in GFPT1 is yet to be discovered. One of the challenges we face is the viability of Gfpt1 -/- knockout mice...
June 14, 2018: Human Molecular Genetics
Jeremiah Hadwen, Sarah Schock, Alan Mears, Robert Yang, Philippe Charron, Liying Zhang, Hualin S Xi, Alex MacKenzie
Rare monogenic diseases affect millions worldwide; although over 4,500 rare disease genotypes are known, disease-modifying drugs are available for only 5% of them. The sheer number of these conditions combined with their rarity precludes traditional costly drug discovery programs. An economically viable alternative is to repurpose established drugs for rare diseases. Many genetic diseases result from increased or decreased protein activity and identification of clinically approved drugs which moderate this pathogenic dosage holds therapeutic potential...
June 13, 2018: Human Molecular Genetics
D'anna M Nelson, Angus Lindsay, Luke M Judge, Dongsheng Duan, Jeffrey S Chamberlain, Dawn A Lowe, James M Ervasti
No abstract text is available yet for this article.
June 12, 2018: Human Molecular Genetics
Erin T Williams, Liliane Glauser, Elpida Tsika, Haisong Jiang, Shariful Islam, Darren J Moore
Mutations in a number of genes cause familial forms of Parkinson's disease (PD), including mutations in the vacuolar protein sorting 35 ortholog (VPS35) and parkin genes. In this study, we identify a novel functional interaction between parkin and VPS35. We demonstrate that parkin interacts with and robustly ubiquitinates VPS35 in human neural cells. Familial parkin mutations are impaired in their ability to ubiquitinate VPS35. Parkin mediates the attachment of an atypical poly-ubiquitin chain to VPS35 with three lysine residues identified within the C-terminal region of VPS35 that are covalently modified by ubiquitin...
June 11, 2018: Human Molecular Genetics
Luz D Orozco, Colin Farrell, Christopher Hale, Liudmilla Rubbi, Arturo Rinaldi, Mete Civelek, Calvin Pan, Larry Lam, Dennis Montoya, Chantle Edillor, Marcus Seldin, Michael Boehnke, Karen L Mohlke, Steve Jacobsen, Johanna Kuusisto, Markku Laakso, Aldons J Lusis, Matteo Pellegrini
No abstract text is available yet for this article.
June 9, 2018: Human Molecular Genetics
Peter M Quinn, C Henrique Alves, Jan Klooster, Jan Wijnholds
The mammalian apical-basal determinant Crumbs homolog-1 (CRB1) plays a crucial role in retinal structure and function by the maintenance of adherens junctions between photoreceptors and Müller glial cells. Patients with mutations in the CRB1 gene develop retinal dystrophies, including early-onset retinitis pigmentosa and Leber congenital amaurosis. Previously, we showed that Crb1 knockout mice developed a slow-progressing retinal phenotype at foci in the inferior retina, whiles specific ablation of Crb2 in immature photoreceptors lead to an early-onset phenotype throughout the retina...
June 8, 2018: Human Molecular Genetics
Coline Macquart, Rene Jüttner, Caroline Le Dour, Maria Chatzifrangkeskou, Alain Schmitt, Michael Gotthardt, Gisèle Bonne, Antoine Muchir
Mutations in the lamin A/C gene (LMNA) cause an autosomal dominant inherited form of dilated cardiomyopathy associated with cardiac conduction disease (hereafter referred to as LMNA cardiomyopathy). Compared with other forms of dilated cardiomyopathy, mutations in LMNA are responsible for a more aggressive clinical course due to a high rate of malignant ventricular arrhythmias. Gap junctions are intercellular channels that allow direct communication between neighboring cells, which are involved in electrical impulse propagation and coordinated contraction of the heart...
June 8, 2018: Human Molecular Genetics
Heike Vogel, Anne Kamitz, Nicole Hallahan, Sandra Lebek, Tanja Schallschmidt, Wenke Jonas, Markus Jähnert, Pascal Gottmann, Lisa Zellner, Timo Kanzleiter, Mareike Damen, Delsi Altenhofen, Ralph Burkhardt, Simone Renner, Maik Dahlhoff, Eckhard Wolf, Timo D Müller, Matthias Blüher, Hans-Georg Joost, Alexandra Chadt, Hadi Al-Hasani, Annette Schürmann
To explore the genetic determinants of obesity and type 2 diabetes (T2D), the German Center for Diabetes Research (DZD) conducted crossbreedings of the obese and diabetes-prone NZO mouse strain with four different lean strains (B6, DBA, C3H, 129P2) which vary in their susceptibility to develop T2D. Genome-wide linkage analyses localized more than 290 QTL for obesity, 190 QTL for diabetes-related traits, and 100 QTL for plasma metabolites in the outcross populations. A computational framework was developed that allowed to refine critical regions and to nominate a small number of candidate genes by integrating reciprocal haplotype mapping and transcriptome data...
June 8, 2018: Human Molecular Genetics
Zohreh Fattahi, Taimoor I Sheikh, Luciana Musante, Memoona Rasheed, Ibrahim Ihsan Taskiran, Ricardo Harripaul, Hao Hu, Somayeh Kazeminasab, Muhammad Rizwan Alam, Masoumeh Hosseini, Farzaneh Larti, Zhila Ghaderi, Arzu Celik, Muhammad Ayub, Muhammad Ansar, Mohammad Haddadi, Thomas F Wienker, Hans Hilger Ropers, Kimia Kahrizi, John B Vincent, H Najmabadi
Exploring genes and pathways underlying Intellectual Disability (ID) provides insight into brain development and function, clarifying the complex puzzle of how cognition develops. As part of ongoing systematic studies to identify candidate ID genes, linkage analysis and next generation sequencing revealed ZBTB11, as a novel candidate ID gene. ZBTB11 encodes a less-studied transcription regulator and the two identified missense variants in this study may disrupt canonical Zn2+-binding residues of its C2H2 zinc finger domain, leading to possible altered DNA binding...
June 8, 2018: Human Molecular Genetics
Lamis Yehia, Supriya Jindal, Anton A Komar, Charis Eng
SEC23B is a component of coat protein complex II (COPII) vesicles that transport secretory proteins from the endoplasmic reticulum (ER) to the Golgi apparatus. Loss-of-function SEC23B mutations cause a rare form of anemia, resulting from decreased SEC23B levels. We recently identified germline heterozygous SEC23B variants as potentially cancer-predisposing. Mutant SEC23B associated with ER stress-mediated tumorigenesis, without decreased SEC23B expression. However, our understanding of the processes behind these observations remain limited...
June 8, 2018: Human Molecular Genetics
Akiko Sumitomo, Hiroshi Yukitake, Kazuko Hirai, Kouta Horike, Keisho Ueta, Youjin Chung, Eiji Warabi, Toru Yanagawa, Shiho Kitaoka, Tomoyuki Furuyashiki, Shuh Narumiya, Tomoo Hirano, Minae Niwa, Etienne Sibille, Takatoshi Hikida, Takeshi Sakurai, Koko Ishizuka, Akira Sawa, Toshifumi Tomoda
Autophagy plays an essential role in intracellular degradation and maintenance of cellular homeostasis in all cells, including neurons. Although a recent study reported a copy number variation of Ulk2, a gene essential for initiating autophagy, associated with a case of schizophrenia (SZ), it remains to be studied whether Ulk2 dysfunction could underlie the pathophysiology of the disease. Here we show that Ulk2 heterozygous (Ulk2+/-) mice have upregulated expression of sequestosome-1/p62, an autophagy-associated stress response protein, predominantly in pyramidal neurons of the prefrontal cortex (PFC), and exhibit behavioral deficits associated with the PFC functions, including attenuated sensorimotor gating and impaired cognition...
June 8, 2018: Human Molecular Genetics
Tom G Richardson, Philip C Haycock, Jie Zheng, Nicholas J Timpson, Tom R Gaunt, George Davey Smith, Caroline L Relton, Gibran Hemani
We have undertaken a systematic Mendelian randomization (MR) study using methylation quantitative trait loci (meQTL) as genetic instruments to assess the relationship between genetic variation, DNA methylation and 139 complex traits. Using two-sample MR, we identified 1,148 associations across 61 traits where genetic variants were associated with both proximal DNA methylation (i.e. cis-meQTL) and complex trait variation (P < 1.39x10-08). Joint likelihood mapping provided evidence that the genetic variant which influenced DNA methylation levels for 348 of these associations across 47 traits was also responsible for variation in complex traits...
June 8, 2018: Human Molecular Genetics
Agustin F Fernandez, Gustavo F Bayón, Marta I Sierra, Rocio G Urdinguio, Estela G Toraño, Maria García, Antonella Carella, Virginia Lopez, Pablo Santamarina, Raúl F Pérez, Thalía Belmonte, Juan Ramon Tejedor, Isabel Cobo, Pablo Menendez, Cristina Mangas, Cecilia Ferrero, Luis Rodrigo, Aurora Astudillo, Ignacio Ortea, Sergio Cueto Díaz, Pablo Rodríguez-Gonzalez, J Ignacio García Alonso, Manuela Mollejo, Bárbara Meléndez, Gemma Dominguez, Felix Bonilla, Mario F Fraga
Aberrant DNA hypermethylation is a hallmark of cancer although the underlying molecular mechanisms are still poorly understood. To study the possible role of 5-hydroxymethylcytosine (5hmC) in this process we analyzed the global and locus-specific genome-wide levels of 5hmC and 5mC in human primary samples from 12 non-tumoral brains and 53 gliomas. We found that the levels of 5hmC identified in non-tumoral samples were significantly reduced in gliomas. Strikingly, hypo-hydroxymethylation at 4,627 (9.3%) CpG sites was associated with aberrant DNA hypermethylation and was strongly enriched in CpG island (CGI) shores...
June 5, 2018: Human Molecular Genetics
Angel Ashikov, Nurulamin Abu Bakar, Xiao-Yan Wen, Marco Niemeijer, Glentino Rodrigues Pinto Osorio, Koroboshka Brand-Arzamendi, Linda Hasadsri, Hana Hansikova, Kimiyo Raymond, Dorothée Vicogne, Marleen E H Simon, Rolph Pfundt, Sharita Timal, Roel Beumers, Christophe Biot, Roel Smeets, Marjan Kersten, Karin Huijben, Peter Ta Linders, Geert van den Bogaart, Sacha A F T van Hijum, Richard Rodenburg, Lambertus P van den Heuvel, Francjan van Spronsen, Tomas Honzik, Francois Foulquier, Monique van Scherpenzeel, Dirk J Lefeber
Genomics methodologies have significantly improved elucidation of Mendelian disorders. The combination with high-throughput functional-omics technologies potentiates the identification and confirmation of causative genetic variants, especially in singleton families of recessive inheritance. In a cohort of 99 individuals with abnormal Golgi glycosylation, 47 of which being unsolved, glycomics profiling was performed of total plasma glycoproteins. Combination with whole-exome sequencing in 31 cases revealed a known genetic defect in 15 individuals...
June 5, 2018: Human Molecular Genetics
Maria Chatzifrangkeskou, David Yadin, Thibaut Marais, Solenne Chardonnet, Mathilde Cohen-Tannoudji, Nathalie Mougenot, Alain Schmitt, Silvia Crasto, Elisa Di Pasquale, Coline Macquart, Yannick Tanguy, Imen Jebeniani, Michel Pucéat, Blanca Morales Rodriguez, Wolfgang H Goldmann, Matteo Dal Ferro, Maria-Grazia Biferi, Petra Knaus, Gisèle Bonne, Howard J Worman, Antoine Muchir
Hyper-activation of extracellular signal-regulated kinase (ERK) 1/2 contributes to heart dysfunction in cardiomyopathy caused by mutations in the lamin A/C gene (LMNA cardiomyopathy). The mechanism of how this affects cardiac function is unknown. We show that active phosphorylated ERK1/2 directly binds to and catalyzes the phosphorylation of the actin depolymerizing factor cofilin-1 on Thr25. Cofilin-1 becomes active and disassembles actin filaments in a large array of cellular and animal models of LMNA cardiomyopathy...
June 5, 2018: Human Molecular Genetics
Michael P Hughes, Dave A Smith, Lauren Morris, Claire Fletcher, Alexandria Colaco, Mylene Huebecker, Julie Tordo, Nuria Palomar, Giulia Massaro, Els Henckaerts, Simon N Waddington, Frances M Platt, Ahad A Rahim
Niemann-Pick type C disease (NP-C) is a fatal neurodegenerative lysosomal storage disorder. It is caused in 95% of cases by a mutation in the NPC1 gene that encodes NPC1, an integral transmembrane protein localised to the limiting membrane of the lysosome. There is no cure for NP-C but there is a disease-modifying drug (miglustat) that slows disease progression but with associated side effects. Here, we demonstrate in a well-characterised mouse model of NP-C that a single administration of AAV-mediated gene therapy to the brain can significantly extend lifespan, improve quality of life, prevent or ameliorate neurodegeneration, reduce biochemical pathology and normalize or improve various indices of motor function...
June 5, 2018: Human Molecular Genetics
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