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Haploinsufficiency

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https://www.readbyqxmd.com/read/28811646/pafah1b1-haploinsufficiency-disrupts-gaba-neurons-and-synaptic-e-i-balance-in-the-dentate-gyrus
#1
Matthew T Dinday, Kelly M Girskis, Sunyoung Lee, Scott C Baraban, Robert F Hunt
Hemizygous mutations in the human gene encoding platelet-activating factor acetylhydrolase IB subunit alpha (Pafah1b1), also called Lissencephaly-1, can cause classical lissencephaly, a severe malformation of cortical development. Children with this disorder suffer from deficits in neuronal migration, severe intellectual disability, intractable epilepsy and early death. While many of these features can be reproduced in Pafah1b1(+/-) mice, the impact of Pafah1b1(+/-) on the function of individual subpopulations of neurons and ultimately brain circuits is largely unknown...
August 15, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28809766/crispr-cas9-editing-of-nf1-gene-identifies-crmp2-as-a-therapeutic-target-in-neurofibromatosis-type-1-related-pain-that-is-reversed-by-s-lacosamide
#2
Aubin Moutal, Xiaofang Yang, Wennan Li, Kerry B Gilbraith, Shizhen Luo, Song Cai, Liberty François-Moutal, Lindsey A Chew, Seul Ki Yeon, Shreya S Bellampalli, Chaoling Qu, Jennifer Y Xie, Mohab M Ibrahim, May Khanna, Ki Duk Park, Frank Porreca, Rajesh Khanna
Neurofibromatosis type 1 (NF1) is a rare autosomal dominant disease linked to mutations of the Nf1 gene. Patients with NF1 commonly experience severe pain. Studies on mice with Nf1 haploinsufficiency have been instructive in identifying sensitization of ion channels as a possible cause underlying the heightened pain suffered by patients with NF1. However, behavioral assessments of Nf1 mice have led to uncertain conclusions about the potential causal role of Nf1 in pain. We used the clustered regularly interspaced short palindromic repeats (CRISPR)-associated 9 (CRISPR/Cas9) genome editing system to create and mechanistically characterize a novel rat model of NF1-related pain...
July 3, 2017: Pain
https://www.readbyqxmd.com/read/28808027/de-novo-mutations-in-inhibitors-of-wnt-bmp-and-ras-erk-signaling-pathways-in-non-syndromic-midline-craniosynostosis
#3
Andrew T Timberlake, Charuta G Furey, Jungmin Choi, Carol Nelson-Williams, Erin Loring, Amy Galm, Kristopher T Kahle, Derek M Steinbacher, Dawid Larysz, John A Persing, Richard P Lifton
Non-syndromic craniosynostosis (NSC) is a frequent congenital malformation in which one or more cranial sutures fuse prematurely. Mutations causing rare syndromic craniosynostoses in humans and engineered mouse models commonly increase signaling of the Wnt, bone morphogenetic protein (BMP), or Ras/ERK pathways, converging on shared nuclear targets that promote bone formation. In contrast, the genetics of NSC is largely unexplored. More than 95% of NSC is sporadic, suggesting a role for de novo mutations. Exome sequencing of 291 parent-offspring trios with midline NSC revealed 15 probands with heterozygous damaging de novo mutations in 12 negative regulators of Wnt, BMP, and Ras/ERK signaling (10...
August 14, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28807867/impairment-of-different-protein-domains-causes-variable-clinical-presentation-within-pitt-hopkins-syndrome-and-suggests-intragenic-molecular-syndromology-of-tcf4
#4
Maria Francesca Bedeschi, Giuseppe Marangi, Maria Rosaria Calvello, Stefania Ricciardi, Francesca Pia Chiara Leone, Marco Baccarin, Silvana Guerneri, Daniela Orteschi, Marina Murdolo, Serena Lattante, Silvia Frangella, Beth Keena, Margaret H Harr, Elaine Zackai, Marcella Zollino
Pitt-Hopkins syndrome is a neurodevelopmental disorder characterized by severe intellectual disability and a distinctive facial gestalt. It is caused by haploinsufficiency of the TCF4 gene. The TCF4 protein has different functional domains, with the NLS (nuclear localization signal) domain coded by exons 7-8 and the bHLH (basic Helix-Loop-Helix) domain coded by exon 18. Several alternatively spliced TCF4 variants have been described, allowing for translation of variable protein isoforms. Typical PTHS patients have impairment of at least the bHLH domain...
August 11, 2017: European Journal of Medical Genetics
https://www.readbyqxmd.com/read/28798347/tonebp-nfat5-haploinsufficiency-attenuates-hippocampal-inflammation-in-high-fat-diet-streptozotocin-induced-diabetic-mice
#5
Jong Youl Lee, Eun Ae Jeong, Kyung Eun Kim, Chin-Ok Yi, Zhen Jin, Jung Eun Lee, Dong Hoon Lee, Hyun Joon Kim, Sang Soo Kang, Gyeong Jae Cho, Wan Sung Choi, Soo Youn Choi, H Moo Kwon, Gu Seob Roh
Recent studies have shown that overexpression of tonicity-responsive enhancer binding protein (TonEBP) is associated with many inflammatory diseases, including diabetes mellitus, which causes neuroinflammation in the hippocampus as well as hepatic steatosis. However, the exact mechanism in diabetic neuroinflammation is unknown. We report that haploinsufficiency of TonEBP inhibits hepatic and hippocampal high-mobility group box-1 (HMGB1) expression in diabetic mice. Here, mice were fed a high-fat diet (HFD) for 16 weeks and received an intraperitoneal injection of 100 mg/kg streptozotocin (STZ) and followed by continued HFD feeding for an additional 4 weeks to induce hyperglycemia and hepatic steatosis...
August 10, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28796572/endoglin-and-alk1-as-therapeutic-targets-for-hereditary-hemorrhagic-telangiectasia
#6
Lidia Ruiz-Llorente, Eunate Gallardo-Vara, Elisa Rossi, David M Smadja, Luisa M Botella, Carmelo Bernabeu
Hereditary Haemorrhagic Telangiectasia (HHT) is as an autosomal dominant trait characterized by frequent nose bleeds, mucocutaneous telangiectases, arteriovenous malformations (AVMs) of the lung, liver and brain, and gastrointestinal bleedings due to telangiectases. HHT is originated by mutations in genes whose encoded proteins are involved in the transforming growth factor β (TGF-β) family signalling of vascular endothelial cells. In spite of the great advances in the diagnosis as well as in the molecular, cellular and animal models of HHT, the current treatments remain just at the palliative level...
August 10, 2017: Expert Opinion on Therapeutic Targets
https://www.readbyqxmd.com/read/28794907/rai1-overexpression-promotes-altered-circadian-gene-expression-and-dyssomnia-in-potocki-lupski-syndrome
#7
Sureni V Mullegama, Joseph T Alaimo, Michael D Fountain, Brooke Burns, Amanda Hebert Balog, Li Chen, Sarah H Elsea
Retinoic acid induced 1 ( RAI1 ) encodes a dosage-sensitive gene that when haploinsufficient results in Smith-Magenis syndrome (SMS) and when overexpressed results in Potocki-Lupski syndrome (PTLS). Phenotypic and molecular evidence illustrates that haploinsufficiency of RAI1 disrupts circadian rhythm through the dysregulation of the master circadian regulator, circadian locomotor output cycles kaput ( CLOCK) , and other core circadian components, contributing to prominent sleep disturbances in SMS. However, the phenotypic and molecular characterization of sleep features in PTLS has not been elucidated...
September 2017: Journal of Pediatric Genetics
https://www.readbyqxmd.com/read/28794905/further-clinical-delineation-of-the-mef2c-haploinsufficiency-syndrome-report-on-new-cases-and-literature-review-of-severe-neurodevelopmental-disorders-presenting-with-seizures-absent-speech-and-involuntary-movements
#8
REVIEW
Irena Vrečar, Josie Innes, Elizabeth A Jones, Helen Kingston, William Reardon, Bronwyn Kerr, Jill Clayton-Smith, Sofia Douzgou
Mutations in the MEF2C ( myocyte enhancer factor 2 ) gene have been established as a cause for an intellectual disability syndrome presenting with seizures, absence of speech, stereotypic movements, hypotonia, and limited ambulation. Phenotypic overlap with Rett's and Angelman's syndromes has been noted. Following the first reports of 5q14.3q15 microdeletions encompassing the MEF2C gene, further cases with point mutations and partial gene deletions of the MEF2C gene have been described. We present the clinical phenotype of our cohort of six patients with MEF2C mutations and compare our findings with previously reported patients as well as with a growing number of genetic conditions presenting with a severe neurodevelopmental, Rett-like, phenotype...
September 2017: Journal of Pediatric Genetics
https://www.readbyqxmd.com/read/28793308/genetic-analysis-of-the-candida-albicans-biofilm-transcription-factor-network-using-simple-and-complex-haploinsufficiency
#9
Virginia E Glazier, Thomas Murante, Daniel Murante, Kristy Koselny, Yuan Liu, Dongyeop Kim, Hyun Koo, Damian J Krysan
Biofilm formation by Candida albicans is a key aspect of its pathobiology and is regulated by an integrated network of transcription factors (Bcr1, Brg1, Efg1, Ndt80, Rob1, and Tec1). To understand the details of how the transcription factors function together to regulate biofilm formation, we used a systematic genetic interaction approach based on generating all possible double heterozygous mutants of the network genes and quantitatively analyzing the genetic interactions between them. Overall, the network is highly susceptible to genetic perturbation with the six network heterozygous mutants all showing alterations in biofilm formation (haploinsufficiency)...
August 9, 2017: PLoS Genetics
https://www.readbyqxmd.com/read/28776093/identification-of-an-atypical-microdeletion-generating-the-rnf135-suz12-chimeric-gene-and-causing-a-position-effect-in-an-nf1-patient-with-overgrowth
#10
Luca Ferrari, Giulietta Scuvera, Arianna Tucci, Donatella Bianchessi, Francesco Rusconi, Francesca Menni, Elena Battaglioli, Donatella Milani, Paola Riva
Neurofibromatosis type I (NF1) microdeletion syndrome, which is present in 4-11% of NF1 patients, is associated with a severe phenotype as it is caused by the deletion of NF1 and other genes in the 17q11.2 region. The variable expressivity of the disease makes it challenging to establish genotype-phenotype correlations, which also affects prognosis and counselling. We here describe a 3-year-old NF1 patient with an atypical deletion and a complex phenotype. The patient showed overgrowth, café au lait spots, inguinal freckling, and neurological abnormalities...
August 3, 2017: Human Genetics
https://www.readbyqxmd.com/read/28766492/mody3-renal-cysts-and-dandy-walker-variants-with-a-microdeletion-spanning-the-hnf1a-gene
#11
Hiro Matsukura, Mariko Nagamori, Kazushi Miya, Tohru Yorifuji
Heterozygous hepatocyte nuclear factor-1-α gene (<italic>HNF1A</italic>) mutations are the most common cause of maturity-onset diabetes of the young (MODY), but they rarely involve extrahepatic manifestations. Renal cysts and diabetes syndrome can be caused by <italic>HNF1B</italic> mutations. No association between MODY3 and Dandy-Walker variants (DWV) has been reported. <italic>HNF1A</italic> mutations might be responsible for renal malformations. In a Japanese girl with glycosuria, developmental delay, mental retardation, renal cysts, and DWV, the <italic>HNF1B</italic> gene had no mutations...
September 2017: Clinical Nephrology
https://www.readbyqxmd.com/read/28766044/analysis-of-gene-expression-and-functional-characterization-of-xpr1-a-pathogenic-gene-for-primary-familial-brain-calcification
#12
Xiang-Ping Yao, Miao Zhao, Chong Wang, Xin-Xin Guo, Hui-Zhen Su, En-Lin Dong, Hai-Ting Chen, Jing-Hui Lai, Yao-Bin Liu, Ning Wang, Wan-Jin Chen
Primary familial brain calcification (PFBC) is a neuropsychiatric disorder characterized by bilateral cerebral calcification with diverse neurologic or psychiatric symptoms. Recently, XPR1 variation has accounted for PFBC as another new causative gene. However, little is known about the distribution and basic function of XPR1 and its interaction with the other three pathogenic genes for PFBC (SLC20A2, PDGFRB and PDGFB). The aim of this study was to further clarify the role of XPR1 in PFBC brain pathology. As a result, gene expression profiles showed that XPR1 mRNA was widely expressed throughout the mouse brain...
August 2, 2017: Cell and Tissue Research
https://www.readbyqxmd.com/read/28758902/gata4-loss-of-function-in-liver-cancer-impedes-precursor-to-hepatocyte-transition
#13
Francis O Enane, Wai Ho Shuen, Xiaorong Gu, Ebrahem Quteba, Bartlomiej Przychodzen, Hideki Makishima, Juraj Bodo, Joanna Ng, Chit Lai Chee, Rebecca Ba, Lip Seng Koh, Janice Lim, Rachael Cheong, Marissa Teo, Zhenbo Hu, Kwok Peng Ng, Jaroslaw Maciejewski, Tomas Radivoyevitch, Alexander Chung, London Lucien Ooi, Yu Meng Tan, Peng Chung Cheow, Pierce Chow, Chung Yip Chan, Kiat Hon Lim, Lisa Yerian, Eric Hsi, Han Chong Toh, Yogen Saunthararajah
The most frequent chromosomal structural loss in hepatocellular carcinoma (HCC) is of the short arm of chromosome 8 (8p). Genes on the remaining homologous chromosome, however, are not recurrently mutated, and the identity of key 8p tumor-suppressor genes (TSG) is unknown. In this work, analysis of minimal commonly deleted 8p segments to identify candidate TSG implicated GATA4, a master transcription factor driver of hepatocyte epithelial lineage fate. In a murine model, liver-conditional deletion of 1 Gata4 allele to model the haploinsufficiency seen in HCC produced enlarged livers with a gene expression profile of persistent precursor proliferation and failed hepatocyte epithelial differentiation...
July 31, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28755412/mechanisms-of-mendelian-dominance
#14
REVIEW
Reiner A Veitia, Sandrine Caburet, James A Birchler
Genetic dominance has long been considered as a qualitative reflection of interallelic interactions. Dominance arises from many multiple sources whose unifying theme is the existence of non-linear relationships between the genotypic and phenotypic values. One of the clearest examples are dominant negative mutations (DNMs) in which a defective subunit poisons a macromolecular complex. Dominance can also be due to the presence of a heterozygous null allele, as is the case of haploinsufficiency. Dominance can also be influenced by epistatic (interloci) interactions...
July 28, 2017: Clinical Genetics
https://www.readbyqxmd.com/read/28743268/the-lysosomal-protein-cathepsin-l-is-a-progranulin-protease
#15
Chris W Lee, Jeannette N Stankowski, Jeannie Chew, Casey N Cook, Ying-Wai Lam, Sandra Almeida, Yari Carlomagno, Kwok-Fai Lau, Mercedes Prudencio, Fen-Biao Gao, Matthew Bogyo, Dennis W Dickson, Leonard Petrucelli
Haploinsufficiency of GRN, the gene encoding progranulin (PGRN), causes frontotemporal lobar degeneration (FTLD), the second most common cause of early-onset dementia. Receptor-mediated lysosomal targeting has been shown to regulate brain PGRN levels, and complete deficiency of PGRN is a direct cause of neuronal ceroid lipofuscinosis (NCL), a lysosomal storage disease. Here we show that the lysosomal cysteine protease cathepsin L (Cat L) can mediate the proteolytic cleavage of intracellular PGRN into poly-granulin and granulin fragments...
July 25, 2017: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/28742278/agenesis-of-the-corpus-callosum-developmental-delay-autism-spectrum-disorder-facial-dysmorphism-and-posterior-polymorphous-corneal-dystrophy-associated-with-zeb1-gene-deletion
#16
Ayeshah Chaudhry, Brian H Chung, Dimitri J Stavropoulos, Marcela P Araya, Asim Ali, Elise Heon, David Chitayat
We report on a girl diagnosed prenatally with agenesis of the corpus callosum (ACC) on fetal ultrasound and MRI. On postnatal follow-up she was noted to have developmental delay, facial dysmorphism, autism spectrum disorder, and posterior polymorphous corneal dystrophy (PPD). Array-comparative genomic hybridization analysis (Array-CGH) showed a 2.05 Mb de novo interstitial deletion at 10p11.23p11.22. The deleted region overlaps 1 OMIM Morbid Map gene, ZEB1 (the zinc finger E-box binding homeobox transcription factor 1), previously associated with posterior polymorphous corneal dystrophy type 3 (PPCD3)...
July 25, 2017: American Journal of Medical Genetics. Part A
https://www.readbyqxmd.com/read/28736618/a-15q14-microdeletion-involving-meis2-identified-in-a-patient-with-autism-spectrum-disorder
#17
Keiko Shimojima, Yumiko Ondo, Nobuhiko Okamoto, Toshiyuki Yamamoto
We describe a 9-year-old male patient with a 15q14 microdeletion including MEIS2. The patient was born with a ventricular septal defect and submucosal cleft. Mild developmental disability and autism spectrum disorder diagnosed in childhood were also considered to be consequences of MEIS2 haploinsufficiency. The relatively mild developmental delay and lack of additional phenotypic features in this patient indicate that only MEIS2 plays an important role in the observed phenotypic features in the heterozygous state...
2017: Human Genome Variation
https://www.readbyqxmd.com/read/28734943/deficits-in-col5a2-expression-result-in-novel-skin-and-adipose-abnormalities-and-predisposition-to-aortic-aneurysms-and-dissections
#18
Arick C Park, Noel Phan, Dawiyat Massoudi, Zhenjie Liu, John F Kernien, Sheila M Adams, Jeffrey M Davidson, David E Birk, Bo Liu, Daniel S Greenspan
Classic Ehlers-Danlos syndrome (cEDS) is characterized by fragile, hyperextensible skin and hypermobile joints. cEDS can be caused by heterozygosity for missense mutations in genes COL5A2 and COL5A1, which encode the α2(V) and α1(V) chains, respectively, of collagen V, and is most often caused by COL5A1 null alleles. However, COL5A2 null alleles have yet to be associated with cEDS or other human pathologies. We previously showed that mice homozygous null for the α2(V) gene Col5a2 are early embryonic lethal, whereas haploinsufficiency caused aberrancies of adult skin, but not a frank cEDS-like phenotype, as skin hyperextensibility at low strain and dermal cauliflower-contoured collagen fibril aggregates, two cEDS hallmarks, were absent...
July 19, 2017: American Journal of Pathology
https://www.readbyqxmd.com/read/28729735/the-wnt-receptor-ryk-is-a-negative-regulator-of-mammalian-dendrite-morphogenesis
#19
Vanessa Lanoue, Michael Langford, Amanda White, Kai Sempert, Lily Fogg, Helen M Cooper
The unique dendritic architecture of a given neuronal subtype determines its synaptic connectivity and ability to integrate into functional neuronal networks. It is now clear that abnormal dendritic structure is associated with neuropsychiatric and neurodegenerative disorders. Currently, however, the nature of the extrinsic factors that limit dendritic growth and branching within predetermined boundaries in the mammalian brain is poorly understood. Here we identify the Wnt receptor Ryk as a novel negative regulator of dendritic arborisation...
July 20, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28720899/p32-heterozygosity-protects-against-age-and-diet-induced-obesity-by-increasing-energy-expenditure
#20
Yong Liu, Patrick L Leslie, Aiwen Jin, Koji Itahana, Lee M Graves, Yanping Zhang
Obesity is increasing in prevalence and has become a global public health problem. The main cause of obesity is a perturbation in energy homeostasis, whereby energy intake exceeds energy expenditure. Although mitochondrial dysfunction has been linked to the deregulation of energy homeostasis, the precise mechanism is poorly understood. Here, we identify mitochondrial p32 (also known as C1QBP) as an important regulator of lipid homeostasis that regulates both aerobic and anaerobic energy metabolism. We show that while whole-body deletion of the p32 results in an embryonic lethal phenotype, mice heterozygous for p32 are resistant to age- and high-fat diet-induced ailments, including obesity, hyperglycemia, and hepatosteatosis...
July 18, 2017: Scientific Reports
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