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Haploinsufficiency

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https://www.readbyqxmd.com/read/28106060/brain-microvasculature-defects-and-glut1-deficiency-syndrome-averted-by-early-repletion-of-the-glucose-transporter-1-protein
#1
Maoxue Tang, Guangping Gao, Carlos B Rueda, Hang Yu, David N Thibodeaux, Tomoyuki Awano, Kristin M Engelstad, Maria-Jose Sanchez-Quintero, Hong Yang, Fanghua Li, Huapeng Li, Qin Su, Kara E Shetler, Lynne Jones, Ryan Seo, Jonathan McConathy, Elizabeth M Hillman, Jeffrey L Noebels, Darryl C De Vivo, Umrao R Monani
Haploinsufficiency of the SLC2A1 gene and paucity of its translated product, the glucose transporter-1 (Glut1) protein, disrupt brain function and cause the neurodevelopmental disorder, Glut1 deficiency syndrome (Glut1 DS). There is little to suggest how reduced Glut1 causes cognitive dysfunction and no optimal treatment for Glut1 DS. We used model mice to demonstrate that low Glut1 protein arrests cerebral angiogenesis, resulting in a profound diminution of the brain microvasculature without compromising the blood-brain barrier...
January 20, 2017: Nature Communications
https://www.readbyqxmd.com/read/28102700/aryl-hydrocarbon-receptor-deficient-mice-are-protected-from-high-fat-diet-induced-changes-in-metabolic-rhythms
#2
Cassie Jaeger, Canxin Xu, Mingwei Sun, Stacey Krager, Shelley A Tischkau
High fat diet (HFD) consumption alters the synchronized circadian timing system resulting in harmful loss, gain or shift of transcriptional oscillations. The aryl hydrocarbon receptor (AhR) shares structural homology to clock genes, containing both PAS domains and basic helix-loop helix structural motifs, allowing for interaction with components of the primary circadian feedback loop. Activation of AhR alters circadian rhythmicity, primarily through inhibition of Clock/Bmal1-mediated regulation of Per1. AhR-deficient mice are protected from diet-induced metabolic dysfunction, exhibiting enhanced insulin sensitivity and glucose tolerance...
January 19, 2017: Chronobiology International
https://www.readbyqxmd.com/read/28099951/complex-x-chromosomal-rearrangements-in-two-women-with-ovarian-dysfunction-implications-of-chromothripsis-chromoanasynthesis-dependent-and-independent-origins-of-complex-genomic-alterations
#3
Erina Suzuki, Hirohito Shima, Machiko Toki, Kunihiko Hanew, Keiko Matsubara, Hiroki Kurahashi, Satoshi Narumi, Tsutomu Ogata, Tsutomu Kamimaki, Maki Fukami
Our current understanding of the phenotypic consequences and the molecular basis of germline complex chromosomal rearrangements remains fragmentary. Here, we report the clinical and molecular characteristics of 2 women with germline complex X-chromosomal rearrangements. Patient 1 presented with nonsyndromic ovarian dysfunction and hyperthyroidism; patient 2 exhibited various Turner syndrome- associated symptoms including ovarian dysfunction, short stature, and autoimmune hypothyroidism. The genomic abnormalities of the patients were characterized by array-based comparative genomic hybridization, high-resolution karyotyping, microsatellite genotyping, X-inactivation analysis, and bisulfite sequencing...
January 19, 2017: Cytogenetic and Genome Research
https://www.readbyqxmd.com/read/28096336/%C3%AE-catenin-haploinsufficiency-promotes-mammary-tumorigenesis-in-an-erbb2-positive-basal-breast-cancer-model
#4
Bui Tung, Babette Schade, Robert D Cardiff, Olulanu H Aina, Virginie Sanguin-Gendreau, William J Muller
Aberrant activation of β-catenin through its activity as a transcription factor has been observed in a large proportion of human malignancies. Despite the improved understanding of the β-catenin signaling pathway over the past three decades, attempts to develop therapies targeting β-catenin remain challenging, and none of these targeted therapies have advanced to the clinic. In this study, we show that part of the challenge in antagonizing β-catenin is caused by its dual functionality as a cell adhesion molecule and a signaling molecule...
January 17, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28094433/bmp15-knockout-like-effect-in-familial-premature-ovarian-insufficiency-with-persistent-ovarian-reserve
#5
Anne Mayer, Baptiste Fouquet, Michel Pugeat, Micheline Misrahi
Premature ovarian insufficiency (POI) affects 1-2% of women under 40 years. BMP15 variants have been described in POI. We studied a family with two sisters compound heterozygous for deletions in the BMP15 gene on chromosome Xp11.22 yielding a human "knockout-like" effect: a c.151_152delGA deletion yielded a p.Glu51IlefsTer27 mutation transmitted by the hemizygous father and a c.189_198delAGGGCATTCAinsTG deletion/insertion yielded a p.Glu64AlafsTer12 mutation transmitted by the heterozygous mother. Both deletions resulted in frameshifts with premature stop codons at positions 78 and 76 in the proregion, precluding mature BMP15 production...
January 17, 2017: Clinical Genetics
https://www.readbyqxmd.com/read/28093780/subacute-demyelinating-polyradiculoneuropathy-complicating-epstein-barr-virus-infection-in-gata2-haploinsufficiency
#6
Mohamed Kazamel, Christopher J Klein, Eduardo E Benarroch, Mrinal M Patnaik, Jennifer A Tracy
INTRODUCTION: Autosomal dominant haploinsufficiency of GATA2 causes monocytopenia and natural killer cell lymphopenia, resulting in predisposition to mycobacterial, fungal, and viral infections. METHODS: We report clinical, serologic, electrophysiologic, and pathologic evaluation of a 29-year-old woman with GATA2 haploinsufficiency and active Epstein-Barr virus (EBV) infection complicated by subacute painful neuropathy. RESULTS: Nerve conduction and electromyography studies showed predominantly demyelinating sensorimotor polyradiculoneuropathy...
January 17, 2017: Muscle & Nerve
https://www.readbyqxmd.com/read/28093361/neil1-is-a-candidate-gene-associated-with-common-variable-immunodeficiency-in-a-patient-with-a-chromosome-15q24-deletion
#7
Rosa Romano, Apostolos Zaravinos, Kyriaki Liadaki, Rozina Caridha, Johanna Lundin, Göran Carlsson, Jacek Winiarski, Qiang Pan-Hammarström, Lennart Hammarström
We report the first patient with an interstitial deletion of chromosome 15q24.1-q24.3 associated with common variable immunodeficiency (CVID). The 18-year old female patient's clinical and immunological phenotype was compared with 8 additional previously published patients with chr15q24 deletions. A CGH analysis estimated the deletion to be 3.767Mb in size (chr15: 74,410,916-78,178,418) and the result was confirmed using qRT-PCR. We defined an immune-related commonly deleted region (ICDR) within the chromosomal band 15q24...
January 13, 2017: Clinical Immunology: the Official Journal of the Clinical Immunology Society
https://www.readbyqxmd.com/read/28091408/novel-mutation-of-cleidocranial-dysplasia-related-frameshift-runt-related-transcription-factor-2-in-a-sporadic-chinese-case
#8
Xue-Yan Qin, Pei-Zeng Jia, Hua-Xiang Zhao, Wei-Ran Li, Feng Chen, Jiu-Xiang Lin
BACKGROUND: Cleidocranial dysplasia (CCD) is an autosomal dominant disease that affects the skeletal system. Common symptoms of CCD include hypoplasia or aplasia of the clavicles, delayed or even absent closure of the fontanels, midface hypoplasia, short stature, and delayed eruption of permanent and supernumerary teeth. Previous studies reported a connection between CCD and the haploinsufficiency of runt-related transcription factor 2 (RUNX2). Here, we report a sporadic Chinese case presenting typical symptoms of CCD...
2017: Chinese Medical Journal
https://www.readbyqxmd.com/read/28081536/wt1-haploinsufficiency-supports-milder-renal-manifestation-in-two-patients-with-denys-drash-syndrome
#9
Mara S Guaragna, Juliana G Ribeiro de Andrade, Bárbara de Freitas Carli, Vera M S Belangero, Andréa T Maciel-Guerra, Gil Guerra-Júnior, Maricilda P de Mello
Denys-Drash syndrome (DDS) is characterized by nephropathy, genital abnormalities, and predisposition to Wilms' tumor. DDS patients usually present heterozygous de novo germline WT1 mutations. The WT1 gene comprises 10 exons encoding the N-terminal transactivation and the C-terminal DNA-binding regions. Two unrelated patients with genital ambiguity and Wilms' tumor were analyzed by sequencing of the WT1 gene, and 3 mutations in exon 1 were identified of which 2 are novel. Patient 1 carried a c.555delC mutation that causes a frameshift and a premature stop codon...
January 13, 2017: Sexual Development: Genetics, Molecular Biology, Evolution, Endocrinology, Embryology, and Pathology of Sex Determination and Differentiation
https://www.readbyqxmd.com/read/28073925/progranulin-regulates-lysosomal-function-and-biogenesis-through-acidification-of-lysosomes
#10
Yoshinori Tanaka, Genjiro Suzuki, Takashi Matsuwaki, Masato Hosokawa, Geidy Serrano, Thomas G Beach, Keitaro Yamanouchi, Masato Hasegawa, Masugi Nishihara
Progranulin (PGRN) haploinsufficiency resulting from loss-of-function mutations in the PGRN gene causes frontotemporal lobar degeneration accompanied by TDP-43 accumulation, and patients with homozygous mutations in the PGRN gene present with neuronal ceroid lipofuscinosis. Although it remains unknown why PGRN deficiency causes neurodegenerative diseases, there is increasing evidence that PGRN is implicated in lysosomal functions. Here, we show PGRN is a secretory lysosomal protein that regulates lysosomal function and biogenesis by controlling the acidification of lysosomes...
January 10, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28073787/col6a5-variants-in-familial-neuropathic-chronic-itch
#11
Filippo Martinelli-Boneschi, Marina Colombi, Marco Castori, Grazia Devigili, Roberto Eleopra, Rayaz A Malik, Marco Ritelli, Nicoletta Zoppi, Chiara Dordoni, Melissa Sorosina, Paola Grammatico, Hassan Fadavi, Monique M Gerrits, Rowida Almomani, Catharina G Faber, Ingemar S J Merkies, Daniela Toniolo, Massimiliano Cocca, Claudio Doglioni, Stephen G Waxman, Sulayman D Dib-Hajj, Michela M Taiana, Jenny Sassone, Raffaella Lombardi, Daniele Cazzato, Andrea Zauli, Silvia Santoro, Margherita Marchi, Giuseppe Lauria
Itch is thought to represent the peculiar response to stimuli conveyed by somatosensory pathways shared with pain through the activation of specific neurons and receptors. It can occur in association with dermatological, systemic and neurological diseases, or be the side effect of certain drugs. However, some patients suffer from chronic idiopathic itch that is frequently ascribed to psychological distress and for which no biomarker is available to date. We investigated three multigenerational families, one of which diagnosed with joint hypermobility syndrome/Ehlers-Danlos syndrome hypermobility type (JHS/EDS-HT), characterized by idiopathic chronic itch with predominantly proximal distribution...
January 9, 2017: Brain: a Journal of Neurology
https://www.readbyqxmd.com/read/28072603/dyserythropoiesis-of-myelodysplastic-syndromes
#12
Carine Lefèvre, Sabrina Bondu, Salomé Le Goff, Olivier Kosmider, Michaela Fontenay
PURPOSE OF REVIEW: Myelodysplastic syndromes (MDS) are heterogeneous diseases of the hematopoietic stem cell in the elderly. Anemia is the main symptom that mostly correlates with dysplastic erythropoiesis in the bone marrow. We will review the recent advances in understanding the diverse mechanisms of dyserythropoiesis. RECENT FINDINGS: Dyserythropoiesis defined as 10% dysplastic erythroid cells in the bone marrow is found in more than 80% of early MDS. Immature erythroblasts accumulate at the expense of mature erythroblasts due to differentiation arrest and apoptosis...
January 7, 2017: Current Opinion in Hematology
https://www.readbyqxmd.com/read/28071689/haploinsufficiency-of-ehmt1-improves-pattern-separation-and-increases-hippocampal-cell-proliferation
#13
Marco Benevento, Charlotte A Oomen, Alexa E Horner, Houshang Amiri, Tessa Jacobs, Charlotte Pauwels, Monica Frega, Tjitske Kleefstra, Maksym V Kopanitsa, Seth G N Grant, Timothy J Bussey, Lisa M Saksida, Catharina E E M Van der Zee, Hans van Bokhoven, Jeffrey C Glennon, Nael Nadif Kasri
Heterozygous mutations or deletions of the human Euchromatin Histone Methyltransferase 1 (EHMT1) gene are the main causes of Kleefstra syndrome, a neurodevelopmental disorder that is characterized by impaired memory, autistic features and mostly severe intellectual disability. Previously, Ehmt1(+/-) heterozygous knockout mice were found to exhibit cranial abnormalities and decreased sociability, phenotypes similar to those observed in Kleefstra syndrome patients. In addition, Ehmt1(+/-) knockout mice were impaired at fear extinction and novel- and spatial object recognition...
January 10, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28069809/the-receptor-interacting-serine-threonine-protein-kinase-1-ripk1-regulates-progranulin-levels
#14
Amanda R Mason, Lisa P Elia, Steven Finkbeiner
Progranulin (PGRN), a secreted growth factor, is a key regulator of inflammation and is genetically linked to two common and devastating neurodegenerative diseases. Haploinsufficiency mutations in GRN, the gene encoding PGRN, cause frontotemporal dementia (FTD) and a GRN SNP confers significantly increased risk for Alzheimer's disease (AD). Because cellular and animal data indicate that increasing PGRN can reverse phenotypes of both FTD and AD, modulating PGRN level has been proposed as a therapeutic strategy for both diseases...
January 9, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28069569/the-crebbp-acetyltransferase-is-a-haploinsufficient-tumor-suppressor-in-b-cell-lymphoma
#15
Jiyuan Zhang, Sofija Vlasevska, Victoria A Wells, Sarah Nataraj, Antony B Holmes, Romain Duval, Stefanie N Meyer, Tongwei Mo, Katia Basso, Paul K Brindle, Shafinaz Hussein, Riccardo Dalla-Favera, Laura Pasqualucci
Inactivating mutations of the CREBBP acetyltransferase are highly frequent in diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL), the two most common germinal-center (GC) derived cancers. However, the role of CREBBP inactivation in lymphomagenesis remains unclear. Here we show that CREBBP regulates enhancer/super-enhancer networks with central roles in GC/post-GC cell fate decisions, including genes involved in signal transduction by the B-cell receptor and CD40 receptor, transcriptional control of GC and plasma cell development, and antigen presentation...
January 9, 2017: Cancer Discovery
https://www.readbyqxmd.com/read/28067899/nitric-oxide-mediates-aortic-disease-in-mice-deficient-in-the-metalloprotease-adamts1-and-in-a-mouse-model-of-marfan-syndrome
#16
Jorge Oller, Nerea Méndez-Barbero, E Josue Ruiz, Silvia Villahoz, Marjolijn Renard, Lizet I Canelas, Ana M Briones, Rut Alberca, Noelia Lozano-Vidal, María A Hurlé, Dianna Milewicz, Arturo Evangelista, Mercedes Salaices, J Francisco Nistal, Luis Jesús Jiménez-Borreguero, Julie De Backer, Miguel R Campanero, Juan Miguel Redondo
Heritable thoracic aortic aneurysms and dissections (TAAD), including Marfan syndrome (MFS), currently lack a cure, and causative mutations have been identified for only a fraction of affected families. Here we identify the metalloproteinase ADAMTS1 and inducible nitric oxide synthase (NOS2) as therapeutic targets in individuals with TAAD. We show that Adamts1 is a major mediator of vascular homeostasis, given that genetic haploinsufficiency of Adamts1 in mice causes TAAD similar to MFS. Aortic nitric oxide and Nos2 levels were higher in Adamts1-deficient mice and in a mouse model of MFS (hereafter referred to as MFS mice), and Nos2 inactivation protected both types of mice from aortic pathology...
January 9, 2017: Nature Medicine
https://www.readbyqxmd.com/read/28062849/interplay-between-a-cytosolic-and-a-cell-surface-carbonic-anhydrase-in-ph-homeostasis-and-acid-tolerance-of-leishmania
#17
Dhiman Sankar Pal, Mazharul Abbasi, Dipon Kumar Mondal, Binitha Anu Varghese, Ritama Paul, Shalini Singh, Rupak Datta
Leishmania parasites have evolved to endure the acidic phagolysosomal environment within host macrophages. How Leishmania cells maintain near-neutral intracellular pH and proliferate in such proton-rich milieu remains poorly understood. We report here that for thriving in acidic condition Leishmania major relies on a cytosolic and a cell surface carbonic anhydrase viz. LmCA1 and LmCA2. Upon exposure to acidic medium, intracellular pH of the LmCA1(+/-), LmCA2(+/-) and LmCA1(+/-): LmCA2(+/-) mutant strains dropped by varying extents that led to cell cycle delay, growth retardation and morphological abnormalities...
January 6, 2017: Journal of Cell Science
https://www.readbyqxmd.com/read/28059119/dysregulation-of-wti-kts-is-associated-with-the-kidney-specific-effects-of-the-lmx1b-r246q-mutation
#18
Gentzon Hall, Brandon Lane, Megan Chryst-Ladd, Guanghong Wu, Jen-Jar Lin, XueJun Qin, Elizabeth R Hauser, Rasheed Gbadegesin
Mutations in the LIM homeobox transcription factor 1-beta (LMX1B) are a cause of nail patellar syndrome, a condition characterized by skeletal changes, glaucoma and focal segmental glomerulosclerosis. Recently, a missense mutation (R246Q) in LMX1B was reported as a cause of glomerular pathologies without extra-renal manifestations, otherwise known as nail patella-like renal disease (NPLRD). We have identified two additional NPLRD families with the R246Q mutation, though the mechanisms by which LMX1BR246Q causes a renal-specific phenotype is unknown...
January 6, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28057753/a-novel-kleefstra-syndrome-associated-variant-that-affects-the-conserved-tplx-motif-within-the-ankyrin-repeat-of-ehmt1-leads-to-abnormal-protein-folding
#19
Patrick R Blackburn, Alexander Tischer, Michael T Zimmermann, Jennifer L Kemppainen, Sujatha Sastry, Amy E Knight Johnson, Margot A Cousin, Nicole J Boczek, Gavin Oliver, Vinod K Misra, Ralitza H Gavrilova, Gwen A Lomberk, Matthew Auton, Raul A Urrutia, Eric W Klee
Kleefstra syndrome (KS) (MIM# 610253), also known as 9q34 deletion syndrome, is an autosomal dominant disorder caused by haploinsufficiency of euchromatic histone methyltransferase-1 (EHMT1). The clinical phenotype of KS includes moderate to severe intellectual disability with absent speech, hypotonia, brachycephaly, congenital heart defects, and dysmorphic facial features with hypertelorism, synophrys, macroglossia, protruding tongue, and prognathism. Only a few cases of de novo missense mutations in EHMT1 giving rise to KS have been described...
January 5, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28057265/tbx1-transcriptional-and-developmental-functions
#20
A Baldini, F G Fulcoli, E Illingworth
Recent data have paved the way to mechanistic studies into the role of Tbx1 during development. Tbx1 is haploinsufficient and is involved in an important genetic disorder. The gene encodes a T-box transcription factor that is expressed from approximately E7.5 in mouse embryos and continues to be expressed in a highly dynamic manner. It is neither a strong transcriptional activator nor a strong repressor, but it regulates a large number of genes through epigenetic modifications. Here, we review recent literature concerning mechanisms of gene regulation by Tbx1 and its role in mammalian development, with a special focus on the cardiac, vascular, and central nervous systems...
2017: Current Topics in Developmental Biology
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