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Haploinsufficiency

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https://www.readbyqxmd.com/read/29782918/bdnf-haploinsufficiency-exerts-a-transient-and-regionally-different-influence-upon-oligodendroglial-lineage-cells-during-postnatal-development
#1
Madeline Nicholson, Rhiannon J Wood, Jessica L Fletcher, Maarten van den Buuse, Simon S Murray, Junhua Xiao
The Brain-Derived Neurotrophic Factor (BDNF) plays important roles in promoting myelination in the developing central nervous system (CNS), however the influence it exerts on oligodendrocyte development in vivo remain unclear. As BDNF knockout mice die in the perinatal period, we undertook a systematic developmental analysis of oligodendroglial lineage cells within multiple CNS regions of BDNF heterozygous (HET) mice. Our data identify that BDNF heterozygosity results in transient reductions in oligodendroglial lineage cell density and progression that are largely restricted to the optic nerve, whereas the corpus callosum, cerebral cortex, basal forebrain and spinal cord white matter tracts are unaffected...
May 18, 2018: Molecular and Cellular Neurosciences
https://www.readbyqxmd.com/read/29770442/current-concepts-in-the-neuropathogenesis-of-mucolipidosis-type-iv
#2
REVIEW
Lauren C Boudewyn, Steven U Walkley
Mucolipidosis type IV (MLIV) is an autosomal recessive, lysosomal storage disorder causing progressively severe intellectual disability, motor and speech deficits, retinal degeneration often culminating in blindness, and systemic disease causing a shortened lifespan. MLIV results from mutations in the gene MCOLN1 encoding the transient receptor potential channel mucolipin-1. It is an ultra-rare disease and is currently known to affect just over 100 diagnosed individuals. The last decade has provided a wealth of research focused on understanding the role of the enigmatic mucolipin-1 protein in cell and brain function and how its absence causes disease...
May 16, 2018: Journal of Neurochemistry
https://www.readbyqxmd.com/read/29770430/nr4a2-haploinsufficiency-is-associated-with-intellectual-disability-and-autism-spectrum-disorder
#3
J Lévy, S Grotto, C Mignot, C Dupont, A Delahaye, B Benzacken, B Keren, D Haye, J Xavier, M Heulin, E Charles, A Verloes, A Maruani, E Pipiras, A-C Tabet
NR4A2, a member of the nuclear receptor superfamily, is involved in modulation of target gene transcription, regulating several developmental processes such as regulation of cellular homeostasis, neuronal development, inflammation and carcinogenesis. 2q24.1 deletions are extremely rare and only one patient with a de novo deletion encompassing only NR4A2 gene was reported so far. We report three additional patients with a de novo deletion encompassing NR4A2: two patients have deletions encompassing only NR4A2 gene and one patient has a deletion including NR4A2 and the first exon of GPD2...
May 16, 2018: Clinical Genetics
https://www.readbyqxmd.com/read/29768403/high-dimensional-single-cell-phenotyping-reveals-extensive-haploinsufficiency
#4
Shinsuke Ohnuki, Yoshikazu Ohya
Haploinsufficiency, a dominant phenotype caused by a heterozygous loss-of-function mutation, has been rarely observed. However, high-dimensional single-cell phenotyping of yeast morphological characteristics revealed haploinsufficiency phenotypes for more than half of 1,112 essential genes under optimal growth conditions. Additionally, 40% of the essential genes with no obvious phenotype under optimal growth conditions displayed haploinsufficiency under severe growth conditions. Haploinsufficiency was detected more frequently in essential genes than in nonessential genes...
May 2018: PLoS Biology
https://www.readbyqxmd.com/read/29768199/the-autism-related-protein-chd8-cooperates-with-c-ebp%C3%AE-to-regulate-adipogenesis
#5
Yasuyuki Kita, Yuta Katayama, Taichi Shiraishi, Takeru Oka, Tetsuya Sato, Mikita Suyama, Yasuyuki Ohkawa, Keishi Miyata, Yuichi Oike, Michiko Shirane, Masaaki Nishiyama, Keiichi I Nakayama
The gene encoding the chromatin remodeler CHD8 is the most frequently mutated gene in individuals with autism spectrum disorder (ASD). Heterozygous mutations in CHD8 give rise to ASD that is often accompanied by macrocephaly, gastrointestinal complaints, and slender habitus. Whereas most phenotypes of CHD8 haploinsufficiency likely result from delayed neurodevelopment, the mechanism underlying slender habitus has remained unknown. Here, we show that CHD8 interacts with CCAAT/enhancer-binding protein β (C/EBPβ) and promotes its transactivation activity during adipocyte differentiation...
May 15, 2018: Cell Reports
https://www.readbyqxmd.com/read/29761115/depdc5-knockdown-causes-mtor-dependent-motor-hyperactivity-in-zebrafish
#6
Hortense de Calbiac, Adriana Dabacan, Elise Marsan, Hervé Tostivint, Gabrielle Devienne, Saeko Ishida, Eric Leguern, Stéphanie Baulac, Raul C Muresan, Edor Kabashi, Sorana Ciura
Objective: DEPDC5 was identified as a major genetic cause of focal epilepsy with deleterious mutations found in a wide range of inherited forms of focal epilepsy, associated with malformation of cortical development in certain cases. Identification of frameshift, truncation, and deletion mutations implicates haploinsufficiency of DEPDC5 in the etiology of focal epilepsy. DEPDC5 is a component of the GATOR1 complex, acting as a negative regulator of mTOR signaling. Methods: Zebrafish represents a vertebrate model suitable for genetic analysis and drug screening in epilepsy-related disorders...
May 2018: Annals of Clinical and Translational Neurology
https://www.readbyqxmd.com/read/29760778/loss-of-dmrt1-gene-in-a-mos-45-xy-9-8-46-xy-r-9-29-47-xy-idic-r-9-%C3%A3-2-1-46-xy-idic-r-9-1-46-xy-1-female-presenting-with-short-stature
#7
Bagas A Marsudi, Hannie Kartapradja, Chrysantine Paramayuda, Jose R L Batubara, Alida R Harahap, Nanis S Marzuki
Background: A 46,XY sex reversal syndrome is characterized by discordant genetic and phenotypic sex, leading to normal external female genitalia, undeveloped gonads and presence of Müllerian structures in an otherwise 46,XY individual. Chromosome 9pter aberrations, such as ring chromosome have been reported to cause 46,XY disorders of sex development (DSD), due to involvement of DMRT1 gene located at the 9p24.3 region. Case presentation: This study presents a unique case of a 12-year-old female with mos 46,XY, (r)9[31]/45,XY,-9[9] karyotype, presenting with intellectual disability and short stature, mimicking Turner syndrome...
2018: Molecular Cytogenetics
https://www.readbyqxmd.com/read/29760409/histone-deacetylase-inhibitor-ms-275-restores-social-and-synaptic-function-in-a-shank3-deficient-mouse-model-of-autism
#8
Kaijie Ma, Luye Qin, Emmanuel Matas, Lara J Duffney, Aiyi Liu, Zhen Yan
Autism is a neurodevelopmental disorder characterized by social deficits and repetitive behaviors. Genetic screening has identified synaptic, transcriptional, and chromatin genes disrupted in autistic patients. Haploinsufficiency of Shank3, which encodes a scaffold protein at glutamatergic synapses, is causally linked to autism. Using a Shank3-deficient mouse model that exhibits prominent autism-like phenotypes, we have found that histone acetylation in the prefrontal cortex (PFC) is abnormally low, which can be reversed by MS-275 (also known as Entinostat, SNDX-275), a class I histone deacetylase (HDAC) inhibitor that is selectively potent in PFC...
April 19, 2018: Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology
https://www.readbyqxmd.com/read/29758565/clinical-and-genetic-analysis-of-a-rare-syndrome-associated-with-neoteny
#9
Richard F Walker, Serban Ciotlos, Qing Mao, Robert Chin, Snezana Drmanac, Nina Barua, Misha R Agarwal, Rebecca Yu Zhang, Zhenyu Li, Michelle Ka Yan Wu, Kevin Sun, Katharine Lee, Staci Nguyen, Jia Sophie Liu, Paolo Carnevali, Radoje Drmanac, Brock A Peters
PurposeWe describe a novel syndrome in seven female patients with extreme developmental delay and neoteny.MethodsAll patients in this study were female, aged 4 to 23 years, were well below the fifth percentile in height and weight, had failed to develop sexually, and lacked the use of language. Karyotype and array chromosome genomic hybridization analysis failed to identify large-scale structural variations. To further understand the underlying cause of disease in these patients, whole-genome sequencing was performed...
April 2018: Genetics in Medicine: Official Journal of the American College of Medical Genetics
https://www.readbyqxmd.com/read/29753320/adverse-effects-of-hif1a-mutation-and-maternal-diabetes-on-the-offspring-heart
#10
Radka Cerychova, Romana Bohuslavova, Frantisek Papousek, David Sedmera, Pavel Abaffy, Vladimir Benes, Frantisek Kolar, Gabriela Pavlinkova
BACKGROUND: Epidemiological studies show that maternal diabetes predisposes offspring to cardiovascular and metabolic disorders. However, the precise mechanisms for the underlying penetrance and disease predisposition remain poorly understood. We examined whether hypoxia-inducible factor 1 alpha, in combination with exposure to a diabetic intrauterine environment, influences the function and molecular structure of the adult offspring heart. METHODS AND RESULTS: In a mouse model, we demonstrated that haploinsufficient (Hif1a+/- ) offspring from a diabetic pregnancy developed left ventricle dysfunction at 12 weeks of age, as manifested by decreased fractional shortening and structural remodeling of the myocardium...
May 12, 2018: Cardiovascular Diabetology
https://www.readbyqxmd.com/read/29744576/the-lysosomal-function-of-progranulin-a-guardian-against-neurodegeneration
#11
REVIEW
Daniel H Paushter, Huan Du, Tuancheng Feng, Fenghua Hu
Progranulin (PGRN), encoded by the GRN gene in humans, is a secreted growth factor implicated in a multitude of processes ranging from regulation of inflammation to wound healing and tumorigenesis. The clinical importance of PGRN became especially evident in 2006, when heterozygous mutations in the GRN gene, resulting in haploinsufficiency, were found to be one of the main causes of frontotemporal lobar degeneration (FTLD). FTLD is a clinically heterogenous disease that results in the progressive atrophy of the frontal and temporal lobes of the brain...
May 9, 2018: Acta Neuropathologica
https://www.readbyqxmd.com/read/29739947/essential-role-of-linx-islr2-in-the-development-of-the-forebrain-anterior-commissure
#12
Shaniya Abudureyimu, Naoya Asai, Atsushi Enomoto, Liang Weng, Hiroki Kobayashi, Xiaoze Wang, Chen Chen, Shinji Mii, Masahide Takahashi
Linx is a member of the leucine-rich repeat and immunoglobulin family of membrane proteins which has critical roles in the development of the peripheral nervous system and forebrain connectivity. A previous study showed that Linx is expressed in projection neurons in the cortex and in cells that comprise the passage to the prethalamus that form the internal capsule, indicating the involvement of Linx in axon guidance and cell-cell communication. In this study, we found that Linx-deficient mice develop severe hydrocephalus and die perinatally by unknown mechanisms...
May 8, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29739871/canonical-notch-signaling-directs-the-fate-of-differentiating-neurocompetent-progenitors-in-the-mammalian-olfactory-epithelium
#13
Daniel B Herrick, Zhen Guo, Woochan Jang, Nikolai Schnittke, James E Schwob
The adult olfactory epithelium (OE) has the remarkable capacity to regenerate fully both neurosensory and non-neuronal cell types after severe epithelial injury. Life-long persistence of two stem cell populations supports OE regeneration when damaged: the horizontal basal cells (HBCs) -- dormant and held in reserve, and globose basal cells (GBCs) -- a heterogeneous population most of which are actively dividing. Both populations regenerate all cell types of the OE after injury, but the mechanisms underlying neuronal vs...
May 8, 2018: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/29739816/-cacna1c-haploinsufficiency-leads-to-pro-social-50-khz-ultrasonic-communication-deficits-in-rats
#14
Theresa M Kisko, Moria D Braun, Susanne Michels, Stephanie H Witt, Marcella Rietschel, Carsten Culmsee, Rainer K W Schwarting, Markus Wöhr
The cross-disorder risk gene CACNA1C is strongly implicated in multiple neuropsychiatric disorders, including autism spectrum disorder (ASD), bipolar disorder (BPD), and schizophrenia (SCZ), with deficits in social functioning being common for all major neuropsychiatric disorders. In the present study, we explored the role of Cacna1c in regulating disorder-relevant behavioral phenotypes, focusing on socio-affective communication after weaning during the critical developmental period of adolescence in rats. To this aim, we used a newly developed genetic Cacna1c rat model and applied a truly reciprocal approach for studying communication through ultrasonic vocalizations, including both sender and receiver...
May 8, 2018: Disease Models & Mechanisms
https://www.readbyqxmd.com/read/29738460/patient-derived-ipscs-and-ins-shedding-new-light-on-the-cellular-etiology-of-neurodegenerative-diseases
#15
Bor Luen Tang
Induced pluripotent stem cells (iPSCs) and induced neuronal (iN) cells are very much touted in terms of their potential promises in therapeutics. However, from a more fundamental perspective, iPSCs and iNs are invaluable tools for the postnatal generation of specific diseased cell types from patients, which may offer insights into disease etiology that are otherwise unobtainable with available animal or human proxies. There are two good recent examples of such important insights with diseased neurons derived via either the iPSC or iN approaches...
May 8, 2018: Cells
https://www.readbyqxmd.com/read/29735433/glycosphingolipid-levels-and-glucocerebrosidase-activity-are-altered-in-normal-aging-of-the-mouse-brain
#16
Penelope J Hallett, Mylene Huebecker, Oeystein R Brekk, Elizabeth B Moloney, Emily M Rocha, David A Priestman, Frances M Platt, Ole Isacson
Aging is the predominant risk factor for both genetic and sporadic Parkinson's disease (PD). The majority of PD cases are nonfamilial, and the connection between aging and PD-associated genes is not well understood. Haploinsufficiency of the GBA gene, leading to a reduction in glucocerebrosidase (GCase) activity, is one of the most common genetic risk factors for PD. Furthermore, GCase activity is also reduced in brain regions of sporadic PD patients, with a corresponding accumulation of its glycosphingolipid (GSL) substrates...
March 29, 2018: Neurobiology of Aging
https://www.readbyqxmd.com/read/29734195/tenascin-x-congenital-adrenal-hyperplasia-and-the-cah-x-syndrome
#17
Walter L Miller, Deborah P Merke
Mutations of the CYP21A2 gene encoding adrenal 21-hydroxylase cause congenital adrenal hyperplasia (CAH). The CYP21A2 gene is partially overlapped by the TNXB gene, which encodes an extracellular matrix protein called Tenascin-X (TNX). Mutations affecting both alleles of TNXB cause a severe, autosomal recessive form of Ehlers-Danlos syndrome (EDS). Rarely, patients with severe, salt-wasting CAH have deletions of CYP21A2 that extend into TNXB, resulting in a "contiguous gene syndrome" consisting of CAH and EDS...
May 7, 2018: Hormone Research in Pædiatrics
https://www.readbyqxmd.com/read/29734022/generalized-epilepsy-and-mild-intellectual-disability-associated-with-13q34-deletion-a-potential-role-for-sox1-and-arhgef7
#18
A Orsini, A Bonuccelli, P Striano, A Azzara, G Costagliola, R Consolini, D G Peroni, A Valetto, V Bertini
Terminal deletions of long arm of chromosome 13 are rare and poorly characterized by cytogenetic studies, making for difficult genotype-phenotype correlations. We report two siblings presenting generalized epilepsy, intellectual disability, and genitourinary tract defects. Array CGH detected a 1.3 Mb deletion at 13q34; it contains two protein-coding genes, SOX1 and ARHGEF7, whose haploinsufficiency can contribute to the epileptic phenotype.
April 26, 2018: Seizure: the Journal of the British Epilepsy Association
https://www.readbyqxmd.com/read/29726930/functional-variants-in-tbx2-are-associated-with-a-syndromic-cardiovascular-and-skeletal-developmental-disorder
#19
Ning Liu, Kelly Schoch, Xi Luo, Loren Pena, Venkata Hemanjani Bhavana, Mary K Kukolich, Sarah Stringer, Zöe Powis, Kelly Radtke, Cameron Mroske, Kristen Deak, Marie T McDonald, Allyn McConkie-Rosell, M Louise Markert, Peter G Kranz, Nicholas Stong, Anna C Need, David Bick, Michelle D Amaral, Elizabeth A Worthey, Shawn Levy, Michael F Wangler, Hugo J Bellen, Shashi Vandana, Shinya Yamamoto
The seventeen genes of the T-box family are transcriptional regulators that are involved in all stages of embryonic development, including craniofacial, brain, heart, skeleton and immune system. Malformation syndromes have been linked to many of the T-box genes. For example, haploinsufficiency of TBX1 is responsible for many structural malformations in DiGeorge syndrome caused by a chromosome 22q11.2 deletion. We report four individuals with an overlapping spectrum of craniofacial dysmorphisms, cardiac anomalies, skeletal malformations, immune deficiency, endocrine abnormalities and developmental impairments, reminiscent of DiGeorge syndrome, who are heterozygotes for TBX2 variants...
May 2, 2018: Human Molecular Genetics
https://www.readbyqxmd.com/read/29726122/interstitial-microdeletion-of-the-1p34-3p34-2-region
#20
Joseph E Jacher, Jeffrey W Innis
BACKGROUND: Interstitial microdeletions of chromosome 1p34.3p34.2 are rare, but are continuing to be identified by the use of chromosome microarray. There have been fewer than 10 individuals identified who have deletions of the 1p34.3p34.2 region; all of these previously described individuals have deletions of the AGO1, AGO3, GRIK3, SLC2A1, or RIMS3 genes. Haploinsufficiency of these genes has been associated with neurodevelopmental delays. METHODS: Chromosome microarray, quantitative PCR, and fluorescence in situ hybridization were performed with DNA extracted from peripheral blood...
May 3, 2018: Molecular Genetics & Genomic Medicine
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