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Haploinsufficiency

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https://www.readbyqxmd.com/read/28926972/juvenile-moyamoya-and-craniosynostosis-in-a-child-with-deletion-1p32p31-expanding-the-clinical-spectrum-of-1p32p31-deletion-syndrome-and-a-review-of-the-literature
#1
Paolo Prontera, Daniela Rogaia, Amedea Mencarelli, Valentina Ottaviani, Ester Sallicandro, Giorgio Guercini, Susanna Esposito, Anna Bersano, Giuseppe Merla, Gabriela Stangoni
Moyamoya angiopathy (MA) is a rare cerebrovascular disorder characterised by the progressive occlusion of the internal carotid artery. Its aetiology is uncertain, but a genetic background seems likely, given the high MA familial rate. To investigate the aetiology of craniosynostosis and juvenile moyamoya in a 14-year-old male patient, we performed an array-comparative genomic hybridisation revealing a de novo interstitial deletion of 8.5 Mb in chromosome region 1p32p31. The deletion involved 34 protein coding genes, including NF1A, whose haploinsufficiency is indicated as being mainly responsible for the 1p32-p31 chromosome deletion syndrome phenotype (OMIM 613735)...
September 17, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28926202/retinal-dysfunction-characterizes-subtypes-of-dominant-optic-atrophy
#2
Maria Lucia Cascavilla, Vincenzo Parisi, Giacinto Triolo, Lucia Ziccardi, Enrico Borrelli, Antonio Di Renzo, Nicole Balducci, Costanza Lamperti, Stefania Bianchi Marzoli, Fatima Darvizeh, Alfredo A Sadun, Valerio Carelli, Francesco Bandello, Piero Barboni
PURPOSE: To assess preganglionic retinal function using multifocal electroretinogram (mfERG) in patients affected by dominant optic atrophy (DOA) stratified by OPA1 gene mutation. METHODS: Multifocal electroretinogram (mfERG) was recorded in 18 DOA patients (DOA group, 35 eyes) and 25 age-matched healthy subjects (control group, 25 eyes). Patients were stratified in two groups based on gene mutation: missense mutation (DOA-M group, 11 eyes) and mutation causing haploinsufficiency (DOA-H group, 24 eyes)...
September 19, 2017: Acta Ophthalmologica
https://www.readbyqxmd.com/read/28923828/attenuated-pdgf-signaling-drives-alveolar-and-microvascular-defects-in-neonatal-chronic-lung%C3%A2-disease
#3
Prajakta Oak, Tina Pritzke, Isabella Thiel, Markus Koschlig, Daphne S Mous, Anita Windhorst, Noopur Jain, Oliver Eickelberg, Kai Foerster, Andreas Schulze, Wolfgang Goepel, Tobias Reicherzer, Harald Ehrhardt, Robbert J Rottier, Peter Ahnert, Ludwig Gortner, Tushar J Desai, Anne Hilgendorff
Neonatal chronic lung disease (nCLD) affects a significant number of neonates receiving mechanical ventilation with oxygen-rich gas (MV-O2). Regardless, the primary molecular driver of the disease remains elusive. We discover significant enrichment for SNPs in the PDGF-Rα gene in preterms with nCLD and directly test the effect of PDGF-Rα haploinsufficiency on the development of nCLD using a preclinical mouse model of MV-O2 In the context of MV-O2, attenuated PDGF signaling independently contributes to defective septation and endothelial cell apoptosis stemming from a PDGF-Rα-dependent reduction in lung VEGF-A...
September 18, 2017: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/28921851/new-intellectual-disability-syndrome-identified-wdr26-haploinsufficiency-is-rare-but-could-provide-explanations-to-some-patients
#4
(no author information available yet)
No abstract text is available yet for this article.
October 2017: American Journal of Medical Genetics. Part A
https://www.readbyqxmd.com/read/28916838/functionally-distinct-tendons-from-elastin-haploinsufficient-mice-exhibit-mild-stiffening-and-tendon-specific-structural-alteration
#5
Jeremy D Eekhoff, Fei Fang, Lindsey G Kahan, M G Espinosa, Austin J Cocciolone, Jessica E Wagenseil, Robert P Mecham, Spencer P Lake
Elastic fibers are present in low quantities in tendon, where they are located both within fascicles near tenocytes and more broadly in the interfascicular matrix. While elastic fibers have long been known to be significant in the mechanics of elastin-rich tissue (i.e. vasculature, skin, lungs), recent studies have suggested a mechanical role for elastic fibers in tendons that is dependent on specific tendon function. However, the exact contribution of elastin to properties of different types of tendons (e...
September 16, 2017: Journal of Biomechanical Engineering
https://www.readbyqxmd.com/read/28915852/a-novel-frameshift-grn-mutation-results-in-frontotemporal-lobar-degeneration-with-a-distinct-clinical-phenotype-in-two-siblings-case-report-and-literature-review
#6
Takashi Hosaka, Kazuhiro Ishii, Takeshi Miura, Naomi Mezaki, Kensaku Kasuga, Takeshi Ikeuchi, Akira Tamaoka
BACKGROUND: Progranulin gene (GRN) mutations are major causes of frontotemporal lobar degeneration. To date, 68 pathogenic GRN mutations have been identified. However, very few of these mutations have been reported in Asians. Moreover, some GRN mutations manifest with familial phenotypic heterogeneity. Here, we present a novel GRN mutation resulting in frontotemporal lobar degeneration with a distinct clinical phenotype, and we review reports of GRN mutations associated with familial phenotypic heterogeneity...
September 15, 2017: BMC Neurology
https://www.readbyqxmd.com/read/28915324/facioscapulohumeral-muscular-dystrophy
#7
Alec M DeSimone, Anna Pakula, Angela Lek, Charles P Emerson
Facioscapulohumeral Muscular Dystrophy is a common form of muscular dystrophy that presents clinically with progressive weakness of the facial, scapular, and humeral muscles, with later involvement of the trunk and lower extremities. While typically inherited as autosomal dominant, facioscapulohumeral muscular dystrophy (FSHD) has a complex genetic and epigenetic etiology that has only recently been well described. The most prevalent form of the disease, FSHD1, is associated with the contraction of the D4Z4 microsatellite repeat array located on a permissive 4qA chromosome...
September 12, 2017: Comprehensive Physiology
https://www.readbyqxmd.com/read/28911199/age-dependent-effects-of-armc5-haploinsufficiency-on-adrenocortical-function
#8
A Berthon, F R Faucz, S Espiard, L Drougat, J Bertherat, C A Stratakis
Inactivating mutations in the Armadillo repeat-containing 5 (ARMC5) gene have recently been discovered in primary macronodular adrenal hyperplasia (PMAH), a cause of Cushing syndrome. Biallelic ARMC5 inactivation in PMAH suggested that ARMC5 may have tumor suppressor functions in the adrenal cortex. We generated and characterized a new mouse model of Armc5 deficiency. Almost all Armc5 knockout mice died during early embryonic development, around 6.5 and 8.5 days. Knockout embryos did not undergo gastrulation, as demonstrated by the absence of mesoderm development at E7...
September 15, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28910570/nine-novel-pax9-mutations-and-a-distinct-tooth-agenesis-genotype-phenotype
#9
S-W Wong, D Han, H Zhang, Y Liu, X Zhang, M Z Miao, Y Wang, N Zhao, L Zeng, B Bai, Y-X Wang, H Liu, S A Frazier-Bowers, H Feng
Tooth agenesis is one of the most common developmental anomalies affecting function and esthetics. The paired-domain transcription factor, Pax9, is critical for patterning and morphogenesis of tooth and taste buds. Mutations of PAX9 have been identified in patients with tooth agenesis. Despite significant progress in the genetics of tooth agenesis, many gaps in knowledge exist in refining the genotype-phenotype correlation between PAX9 and tooth agenesis. In the present study, we complete genetic and phenotypic characterization of multiplex Chinese families with nonsyndromic (NS) tooth agenesis...
September 1, 2017: Journal of Dental Research
https://www.readbyqxmd.com/read/28906020/diagnostic-impact-of-anterior-segment-angiography-of-limbal-stem-cell-insufficiency-in-pax6-related-aniridia
#10
Barbara Käsmann-Kellner, Lorenz Latta, Fabian Fries, Arne Viestenz, Berthold Seitz
BACKGROUND: PAX6 is a master gene of ocular development and postnatal ocular equilibrium. Congenital aniridia is the hallmark of PAX6 gene haploinsufficiency (Chr. 11 p. 13), but PAX6-associated aniridia is a profound, progressive pan-ocular developmental disorder often leading to blindness. Limbal stem cell insufficiency and corneal findings in PAX6 syndrome: There is congenital visual impairment with advancing loss of vision mainly due to secondary glaucoma and to corneal blindness caused by limbal stem cell insufficiency (LSCI)...
September 14, 2017: Clinical Anatomy
https://www.readbyqxmd.com/read/28899992/depletion-of-progranulin-reduces-glun2b-containing-nmda-receptor-density-tau-phosphorylation-and-dendritic-arborization-in-mouse-primary-cortical-neurons
#11
Francesca Longhena, Michela Zaltieri, Jessica Grigoletto, Gaia Faustini, Luca La Via, Roberta Ghidoni, Luisa Benussi, Cristina Missale, PierFranco Spano, Arianna Bellucci
Loss-of-function mutations in the progranulin (PGRN) gene are a common cause of familial frontotemporal lobar degeneration (FTLD). This an age-related neurodegenerative disorder characterized by brain atrophy in the frontal and temporal lobes and with typical symptoms such as cognitive and memory impairment, profound behavioral abnormalities and personality changes, that are thought to be related to connectome dysfunctions. Recently, PGRN reduction has been found to induce a behavioural phenotype reminiscent of FTLD symptoms in mice by affecting neuron spine density and morphology, suggesting that the protein can influence neuronal structural plasticity...
September 12, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28898438/collagen-xi-mutation-lowers-susceptibility-to-load-induced-cartilage-damage-in-mice
#12
Derek T Holyoak, Miguel Otero, Naa Shidaa Armar, Sophia N Ziemian, Ariana Otto, Devinne Cullinane, Timothy M Wright, Steven R Goldring, Mary B Goldring, Marjolein C H van der Meulen
Interactions among risk factors for osteoarthritis (OA) are not well understood. We investigated the combined impact of two prevalent risk factors: mechanical loading and genetically abnormal cartilage tissue properties. We used cyclic tibial compression to simulate mechanical loading in the cho/+ (Col11a1 haploinsufficient) mouse, which has abnormal collagen fibrils in cartilage due to a point mutation in the Col11a1 gene. We hypothesized that the mutant collagen would not alter phenotypic bone properties and that cho/+ mice, which develop early onset OA, would develop enhanced load-induced cartilage damage compared to their littermates...
September 12, 2017: Journal of Orthopaedic Research: Official Publication of the Orthopaedic Research Society
https://www.readbyqxmd.com/read/28898113/interferon-regulatory-factor-6-is-necessary-for-salivary-glands-and-pancreas-development
#13
K A Metwalli, M A Do, K Nguyen, S Mallick, K Kin, N Farokhnia, G Jun, W D Fakhouri
Interferon regulatory factor 6 ( IRF6) acts as a tumor suppressor and controls cell differentiation in ectodermal and craniofacial tissues by regulating expression of target genes. Haploinsufficiency of IRF6 causes Van der Woude and popliteal pterygium syndrome, 2 syndromic forms of cleft lip and palate. Around 85% of patients with Van der Woude express pits on the lower lip that continuously or intermittently drain saliva, and patients with the common cleft lip and palate have a higher prevalence of dental caries and gingivitis...
September 1, 2017: Journal of Dental Research
https://www.readbyqxmd.com/read/28893539/functional-analysis-of-a-sox10-gene-mutation-associated-with-waardenburg-syndrome-ii
#14
Xue-Ping Wang, Zi-Qi Hao, Ya-Lan Liu, Ling-Yun Mei, Chu-Feng He, Zhi-Jie Niu, Jie Sun, Yu-Lin Zhao, Yong Feng
Waardenburg syndrome (WS) is an autosomal dominant inherited non-syndromic type of hereditary hearing loss characterized by varying combinations of sensorineural hearing loss and abnormal pigmentation of the hair, skin, and inner ear. WS is classified into four subtypes (WS1-WS4) based on additional symptoms. WS2 is characterized by the absence of additional symptoms. Recently, we identified a SOX10 missense mutation c.422T > C (p.L141P) associated with WS2. We performed functional assays and found the mutant loses DNA-binding capacity, shows aberrant cytoplasmic and nuclear localization, and fails to interact with PAX3...
September 9, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28890134/modifiers-of-grn-associated-frontotemporal-lobar-degeneration
#15
REVIEW
Eline Wauters, Sara Van Mossevelde, Julie Van der Zee, Marc Cruts, Christine Van Broeckhoven
Heterozygous loss-of-function (LOF) mutations in the human progranulin gene (GRN) cause frontotemporal lobar degeneration (FTLD) by a mechanism of haploinsufficiency. Patients present most frequently with frontotemporal dementia, which is the second most common neurodegenerative dementia at young age. Currently, no disease-modifying therapies are available for these patients. Stimulating GRN protein expression or inhibiting its breakdown is an obvious therapeutic strategy, and is indeed the focus of current preclinical research and clinical trials...
September 7, 2017: Trends in Molecular Medicine
https://www.readbyqxmd.com/read/28889378/defining-the-pathways-of-urogenital-schistosomiasis-associated-urothelial-carcinogenesis-through-transgenic-and-bladder-wall-egg-injection-models
#16
Evaristus C Mbanefo, Michael H Hsieh
Urogenital schistosomiasis (infection with Schistosoma haematobium) is a major cause of bladder carcinogenesis. However, the exact mechanisms of the sequelae leading up to the development of bladder cancer are poorly understood, mainly because of a dearth of tractable mouse models. We developed a mouse model of urogenital schistosomiasis through intramural injection of parasite eggs into the bladder wall to mimic the trapping of parasite eggs in the bladder. This approach recapitulates many of the sequelae observed in infected humans...
2018: Methods in Molecular Biology
https://www.readbyqxmd.com/read/28886095/reduced-slc1a1-expression-is-associated-with-neuroinflammation-and-impaired-sensorimotor-gating-and-cognitive-performance-in-mice-implications-for-schizophrenia
#17
Parisa Afshari, Wei-Dong Yao, Frank A Middleton
We previously reported a 84-Kb hemi-deletion copy number variant at the SLC1A1 gene locus that reduces its expression and appeared causally linked to schizophrenia. In this report, we characterize the in vivo and in vitro consequences of reduced expression of Slc1a1 in mice. Heterozygous (HET) Slc1a1+/- mice, which more closely model the hemi-deletion we found in human subjects, were examined in a series of behavioral, anatomical and biochemical assays. Knockout (KO) mice were also included in the behavioral studies for comparative purposes...
2017: PloS One
https://www.readbyqxmd.com/read/28884888/foxp1-haploinsufficiency-phenotypes-beyond-behavior-and-intellectual-disability
#18
Angela Myers, Christèle du Souich, Connie L Yang, Lior Borovik, Jill Mwenifumbo, Rosemarie Rupps, Causes Study, Anna Lehman, Cornelius F Boerkoel
The forkhead box (FOX) transcription factors have roles in development, carcinogenesis, metabolism, and immunity. In humans FOXP1 mutations have been associated with language and speech defects, intellectual disability, autism spectrum disorder, facial dysmorphisms, and congenital anomalies of the kidney and urinary tract. In mice, Foxp1 plays critical roles in development of the spinal motor neurons, lymphocytes, cardiomyocytes, foregut, and skeleton. We hypothesized therefore that mutations of FOXP1 affect additional tissues in some humans...
September 8, 2017: American Journal of Medical Genetics. Part A
https://www.readbyqxmd.com/read/28884684/inhibition-of-dyrk1a-disrupts-neural-lineage-specification-in-human-pluripotent-stem-cells
#19
Stephanie F Bellmaine, Dmitry A Ovchinnikov, David T Manallack, Claire E Cuddy, Andrew G Elefanty, Edouard G Stanley, Ernst J Wolvetang, Spencer J Williams, Martin Pera
Genetic analysis has revealed that the dual specificity protein kinase DYRK1A has multiple roles in the development of the central nervous system. Increased DYRK1A gene dosage, such as occurs in Down syndrome, affects neural progenitor cell differentiation, while haploinsufficiency of DYRK1A is associated with severe microcephaly. Using a set of known and newly synthesized DYRK1A inhibitors, along with CRISPR-mediated gene activation and shRNA knockdown of DYRK1A, we show that chemical inhibition or genetic knockdown of DYRK1A interferes with neural specification of human pluripotent stem cells, a process equating to the earliest stage of human brain development...
September 8, 2017: ELife
https://www.readbyqxmd.com/read/28881594/the-mir-106a-363-xpcl1-mirna-cluster-induces-murine-t-cell-lymphoma-despite-transcriptional-activation-of-the-p27-kip1-cell-cycle-inhibitor
#20
Daniel A Kuppers, Thomas M Schmitt, Harry C Hwang, Lavanya Samraj, Bruce E Clurman, Matthew L Fero
The miR-106a~363 cluster encodes 6 miRNAs on the X-chromosome which are abundant in blood cells and overexpressed in a variety of malignancies. The constituent miRNA of miR-106a~363 have functional activities in vitro that are predicted to be both oncogenic and tumor suppressive, yet little is known about their physiological functions in vivo. Mature miR-106a~363 (Mirc2) miRNAs are processed from an intragenic, non-protein encoding gene referred to as Xpcl1 (or Kis2), situated at an X-chromosomal locus frequently targeted by retroviruses in murine lymphomas...
August 1, 2017: Oncotarget
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