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Haploinsufficiency

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https://www.readbyqxmd.com/read/28213670/emerging-genotype-phenotype-relationships-in-patients-with-large-nf1-deletions
#1
REVIEW
Hildegard Kehrer-Sawatzki, Victor-Felix Mautner, David N Cooper
The most frequent recurring mutations in neurofibromatosis type 1 (NF1) are large deletions encompassing the NF1 gene and its flanking regions (NF1 microdeletions). The majority of these deletions encompass 1.4-Mb and are associated with the loss of 14 protein-coding genes and four microRNA genes. Patients with germline type-1 NF1 microdeletions frequently exhibit dysmorphic facial features, overgrowth/tall-for-age stature, significant delay in cognitive development, large hands and feet, hyperflexibility of joints and muscular hypotonia...
February 17, 2017: Human Genetics
https://www.readbyqxmd.com/read/28211987/10-year-old-female-with-intragenic-kansl1-mutation-no-kansl1-related-intellectual-disability-and-preserved-verbal-intelligence
#2
Colleen Keen, Carole Samango-Sprouse, Holly Dubbs, Elaine H Zackai
Koolen-de Vries Syndrome (KdVS), also referred to as 17q21.31 microdeletion syndrome, is caused by haploinsufficiency of the KANSL1 gene. This genetic disorder is associated with a clinical phenotype including facial dysmorphism, developmental delay, and friendly disposition, as well as mild-to-moderate intellectual disability. We present the case of a 10 year 8 month old female with KdVS due to a de novo intragenic KANSL1 mutation. At this time, she does not present with intellectual disability, and her verbal intelligence is relatively preserved, although she has perceptual deficits, developmental dyspraxia, and severe speech disorder...
March 2017: American Journal of Medical Genetics. Part A
https://www.readbyqxmd.com/read/28209762/identification-of-genes-in-saccharomyces-cerevisiae-that-are-haploinsufficient-for-overcoming-amino-acid-starvation
#3
Nancy S Bae, Andrew P Seberg, Leslie P Carroll, Mark J Swanson
The yeast Saccharomyces cerevisiae responds to amino acid deprivation by activating a pathway conserved in eukaryotes to overcome the starvation stress. We have screened the entire yeast heterozygous deletion collection to identify strains haploinsufficient for growth in the presence of sulfometuron methyl, which causes starvation for isoleucine and valine. We have discovered that cells devoid of MET15 are sensitive to sulfometuron methyl, and loss of heterozygosity at the MET15 locus can complicate screening the heterozygous deletion collection...
February 16, 2017: G3: Genes—Genomes—Genetics
https://www.readbyqxmd.com/read/28198375/haploinsufficiency-networks-identify-targetable-patterns-of-allelic-deficiency-in-low-mutation-ovarian-cancer
#4
Joe Ryan Delaney, Chandni B Patel, Katelyn McCabe Willis, Mina Haghighiabyaneh, Joshua Axelrod, Isabelle Tancioni, Dan Lu, Jaidev Bapat, Shanique Young, Octavia Cadassou, Alena Bartakova, Parthiv Sheth, Carley Haft, Sandra Hui, Cheryl Saenz, David D Schlaepfer, Olivier Harismendy, Dwayne G Stupack
Identification of specific oncogenic gene changes has enabled the modern generation of targeted cancer therapeutics. In high-grade serous ovarian cancer (OV), the bulk of genetic changes is not somatic point mutations, but rather somatic copy-number alterations (SCNAs). The impact of SCNAs on tumour biology remains poorly understood. Here we build haploinsufficiency network analyses to identify which SCNA patterns are most disruptive in OV. Of all KEGG pathways (N=187), autophagy is the most significantly disrupted by coincident gene deletions...
February 15, 2017: Nature Communications
https://www.readbyqxmd.com/read/28196600/genome-editing-in-hpscs-reveals-gata6-haploinsufficiency-and-a-genetic-interaction-with-gata4-in-human-pancreatic-development
#5
Zhong-Dong Shi, Kihyun Lee, Dapeng Yang, Sadaf Amin, Nipun Verma, Qing V Li, Zengrong Zhu, Chew-Li Soh, Ritu Kumar, Todd Evans, Shuibing Chen, Danwei Huangfu
Human disease phenotypes associated with haploinsufficient gene requirements are often not recapitulated well in animal models. Here, we have investigated the association between human GATA6 haploinsufficiency and a wide range of clinical phenotypes that include neonatal and adult-onset diabetes using CRISPR (clustered regularly interspaced short palindromic repeat)/Cas9-mediated genome editing coupled with human pluripotent stem cell (hPSC) directed differentiation. We found that loss of one GATA6 allele specifically affects the differentiation of human pancreatic progenitors from the early PDX1+ stage to the more mature PDX1+NKX6...
February 8, 2017: Cell Stem Cell
https://www.readbyqxmd.com/read/28195154/zinc-finger-protein-zpr9-functions-as-an-activator-of-ampk-related-serine-threonine-kinase-mpk38-melk-involved-in-ask1-tgf-%C3%AE-p53-signaling-pathways
#6
Hyun-A Seong, Ravi Manoharan, Hyunjung Ha
Murine protein serine-threonine kinase 38 (MPK38), an AMP-activated protein kinase (AMPK)-related kinase, has been implicated in the induction of apoptosis signal-regulating kinase 1 (ASK1)-, transforming growth factor-β (TGF-β)-, and p53-mediated activity involved in metabolic homeostasis. Here, zinc finger protein ZPR9 was found to be an activator of MPK38. The association of MPK38 and ZPR9 was mediated by cysteine residues present in each of these two proteins, Cys(269) and Cys(286) of MPK38 and Cys(305) and Cys(308) of ZPR9...
February 14, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28186690/reduced-levels-of-cacna1c-attenuate-mesolimbic-dopamine-system-function
#7
Chantelle E Terrillion, David T Dao, Roger Cachope, Mary Kay Lobo, Adam C Puche, Joseph F Cheer, Todd D Gould
Genetic variation in CACNA1C, which codes for the L-type calcium channel (LTCC) Cav 1.2, is associated with clinical diagnoses of bipolar disorder, depression, and schizophrenia. Dysregulation of the mesolimbic dopamine (DA) system is linked to these syndromes and LTCCs are required for normal DAergic neurotransmission between the ventral tegmental area (VTA) and nucleus accumbens (NAc). It is unclear, however, how variations in CACNA1C genotype, and potential subsequent changes in expression levels in these regions, modify risk...
February 10, 2017: Genes, Brain, and Behavior
https://www.readbyqxmd.com/read/28181366/molecular-phenotype-and-bleeding-risks-of-an-inherited-platelet-disorder-in-a-family-with-a-runx1-frameshift-mutation
#8
M S Badin, J K Iyer, M Chong, L Graf, G E Rivard, J S Waye, A D Paterson, G Pare, C P M Hayward
INTRODUCTION: Inherited defects in RUNX1 are important causes of platelet function disorders. AIM: Our goals were to evaluate RUNX1-related platelet disorders among individuals evaluated for uncharacterized, inherited platelet function disorders and test a proof of concept that bleeding risks could be quantitatively estimated for typical families with an inherited platelet function disorder. METHODS: Index cases with an uncharacterized inherited platelet function disorder were subjected to exome sequencing with confirmation of RUNX1 mutations by Sanger sequencing...
February 8, 2017: Haemophilia: the Official Journal of the World Federation of Hemophilia
https://www.readbyqxmd.com/read/28181292/tumor-associated-ape1-variant-exhibits-reduced-complementation-efficiency-but-does-not-promote-cancer-cell-phenotypes
#9
Jennifer L Illuzzi, Daniel R McNeill, Paul Bastian, Boris Brenerman, Robert Wersto, Helen R Russell, Fred Bunz, Peter J McKinnon, Kevin G Becker, David M Wilson
Base excision repair (BER) is the major pathway for coping with most forms of endogenous DNA damage, and defects in the process have been associated with carcinogenesis. Apurinic/apyrimidinic endonuclease 1 (APE1) is a central participant in BER, functioning as a critical endonuclease in the processing of noncoding abasic sites in DNA. Evidence has suggested that APE1 missense mutants, as well as altered expression or localization of the protein, can contribute to disease manifestation. We report herein that the tumor-associated APE1 variant, R237C, shows reduced complementation efficiency of the methyl methanesulfonate hypersensitivity and impaired cell growth exhibited by APE1-deficient mouse embryonic fibroblasts...
February 9, 2017: Environmental and Molecular Mutagenesis
https://www.readbyqxmd.com/read/28178280/knockdown-of-hspa9-induces-tp53-dependent-apoptosis-in-human-hematopoietic-progenitor-cells
#10
Tuoen Liu, Kilannin Krysiak, Cara Lunn Shirai, Sanghyun Kim, Jin Shao, Matthew Ndonwi, Matthew J Walter
Myelodysplastic syndromes (MDS) are the most common adult myeloid blood cancers in the US. Patients have increased apoptosis in their bone marrow cells leading to low peripheral blood counts. The full complement of gene mutations that contribute to increased apoptosis in MDS remains unknown. Up to 25% of MDS patients harbor and acquired interstitial deletion on the long arm of chromosome 5 [del(5q)], creating haploinsufficiency for a large set of genes including HSPA9. Knockdown of HSPA9 in primary human CD34+ hematopoietic progenitor cells significantly inhibits growth and increases apoptosis...
2017: PloS One
https://www.readbyqxmd.com/read/28173761/a-novel-complex-runx2-gene-mutation-causes-cleidocranial-dysplasia
#11
Wen'an Xu, Qiuyue Chen, Cuixian Liu, Jiajing Chen, Fu Xiong, Buling Wu
BACKGROUND: Haploinsufficiency of the runt-related transcription factor 2 (RUNX2) gene is known to cause cleidocranial dysplasia (CCD). Here, we investigated a complex, heterozygous RUNX2 gene mutation in a Chinese family with CCD and the pathogenesis associated with the variations. METHODS: Genomic DNA extracted from peripheral venous blood was taken from the proband, her parents and 3 siblings, and 150 normal controls. Analysis of their respective RUNX2 gene sequences was performed by PCR amplification and Sanger sequencing...
February 7, 2017: BMC Medical Genetics
https://www.readbyqxmd.com/read/28169375/the-rb1-tumour-suppressor-gene-modifies-telomeric-chromatin-architecture-by-regulating-terra-expression
#12
I Gonzalez-Vasconcellos, R Schneider, N Anastasov, S Alonso-Rodriguez, B Sanli-Bonazzi, J L Fernández, M J Atkinson
The tumour suppressor gene (Rb1) is necessary for the maintenance of telomere integrity in osteoblastic cells. We now show that the compaction of telomeric chromatin and the appropriate histone modifications of telomeric DNA are both dependent upon Rb1-mediated transcription of the telomere-derived long non-coding RNA TERRA. Expression of TERRA was reduced in Rb1 haploinsufficient cells, and further decreased by shRNA-mediated reduction of residual Rb1 expression. Restoration of Rb1 levels through lentiviral transduction was sufficient to reestablish both transcription of TERRA and condensation of telomeric chromatin...
February 7, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28167794/gata4-potentiates-second-heart-field-proliferation-and-hedgehog-signaling-for-cardiac-septation
#13
Lun Zhou, Jielin Liu, Menglan Xiang, Patrick Olson, Alexander Guzzetta, Ke Zhang, Ivan P Moskowitz, Linglin Xie
GATA4, an essential cardiogenic transcription factor, provides a model for dominant transcription factor mutations in human disease. Dominant GATA4 mutations cause congenital heart disease (CHD), specifically atrial and atrioventricular septal defects (ASDs and AVSDs). We found that second heart field (SHF)-specific Gata4 heterozygote embryos recapitulated the AVSDs observed in germline Gata4 heterozygote embryos. A proliferation defect of SHF atrial septum progenitors and hypoplasia of the dorsal mesenchymal protrusion, rather than anlage of the atrioventricular septum, were observed in this model...
February 6, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28166199/klf6-depletion-promotes-nf-%C3%AE%C2%BAb-signaling-in-glioblastoma
#14
A P Masilamani, R Ferrarese, E Kling, N K Thudi, H Kim, D M Scholtens, F Dai, M Hadler, T Unterkircher, L Platania, A Weyerbrock, M Prinz, G Y Gillespie, G R Harsh Iv, M Bredel, M S Carro
Dysregulation of the NF-κB transcription factor occurs in many cancer types. Krüppel-like family of transcription factors (KLFs) regulate the expression of genes involved in cell proliferation, differentiation and survival. Here, we report a new mechanism of NF-κB activation in glioblastoma through depletion of the KLF6 tumor suppressor. We show that KLF6 transactivates multiple genes negatively controlling the NF-κB pathway and consequently reduces NF-κB nuclear localization and downregulates NF-κB targets...
February 6, 2017: Oncogene
https://www.readbyqxmd.com/read/28166196/the-ptprot-tyrosine-phosphatase-functions-as-an-obligate-haploinsufficient-tumor-suppressor-in-vivo-in-b-cell-chronic-lymphocytic-leukemia
#15
J Wakim, E Arman, S Becker-Herman, M P Kramer, E Bakos, I Shachar, A Elson
The tyrosine phosphatase PTPROt is a suggested tumor suppressor (TS) in B-cell chronic lymphocytic leukemia (CLL), and its expression is reduced in this disease. In order to examine how reduced PTPROt expression affects CLL in vivo we induced CLL in PTPROt-targeted mice. Unexpectedly, loss of both Ptprot alleles delayed disease detection and progression and lengthened survival relative to mice carrying two intact alleles, indicating that PTPROt fulfills a novel tumor-promoting role in CLL. Tumor cells from mice lacking PTPROt exhibited reduced B-cell receptor (BCR)-induced signaling, as well as increased apoptosis and autophagy...
February 6, 2017: Oncogene
https://www.readbyqxmd.com/read/28165391/charcot-marie-tooth-2b-peripheral-sensory-neuropathy-how-rab7-mutations-impact-ngf-signaling
#16
REVIEW
Harry Liu, Chengbiao Wu
Charcot-Marie-Tooth 2B peripheral sensory neuropathy (CMT2B) is a debilitating autosomal dominant hereditary sensory neuropathy. Patients with this disease lose pain sensation and frequently need amputation. Axonal dysfunction and degeneration of peripheral sensory neurons is a major clinical manifestation of CMT2B. However, the cellular and molecular pathogenic mechanisms remain undefined. CMT2B is caused by missense point mutations (L129F, K157N, N161T/I, V162M) in Rab7 GTPase. Strong evidence suggests that the Rab7 mutation(s) enhances the cellular levels of activated Rab7 proteins, thus resulting in increased lysosomal activity and autophagy...
February 4, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28162896/haploinsufficiency-of-sirt1-enhances-glutamine-metabolism-and-promotes-cancer-development
#17
Natalie S X Ren, Ming Ji, Erik J Tokar, Evan L Busch, Xiaojiang Xu, DeAsia Lewis, Xiangchun Li, Aiwen Jin, Yanping Zhang, William K K Wu, Weichun Huang, Leping Li, David C Fargo, Temitope O Keku, Robert S Sandler, Xiaoling Li
SIRT1, the most conserved mammalian NAD(+)-dependent protein deacetylase, plays a vital role in the regulation of metabolism, stress responses, and genome stability. However, the role of SIRT1 in the multi-step process leading to transformation and/or tumorigenesis, as either a tumor suppressor or tumor promoter, is complex and may be dependent upon the context in which SIRT1 activity is altered, and the role of SIRT1 in tumor metabolism is unknown. Here, we demonstrate that SIRT1 dose-dependently regulates cellular glutamine metabolism and apoptosis, which in turn differentially impact cell proliferation and cancer development...
January 31, 2017: Current Biology: CB
https://www.readbyqxmd.com/read/28159702/a-case-of-feingold-type-2-syndrome-associated-with-keratoconus-refines-keratoconus-type-7-locus-on-chromosome-13q
#18
Fabio Sirchia, Eleonora Di Gregorio, Gabriella Restagno, Enrico Grosso, Patrizia Pappi, Flavia Talarico, Elisa Savin, Simona Cavalieri, Elisa Giorgio, Cecilia Mancini, Barbara Pasini, Jodhbir S Mehta, Alfredo Brusco
We report on a 58-year old woman with microcephaly, mild dysmorphic features, bilateral keratoconus, digital abnormalities, short stature and mild cognitive delay. Except for keratoconus, the phenotype was suggestive for Feingold syndrome type 2 (FGLDS2, MIM 614326), a rare autosomal dominant disorder described in six patients worldwide, due to the haploinsufficiency of MIR17HG, a micro RNA encoding gene. Karyotype showed a de novo deletion on chromosome 13q, further defined by array-Comparative Genomic Hybridization (a-CGH) to a 17...
January 31, 2017: European Journal of Medical Genetics
https://www.readbyqxmd.com/read/28156030/er-to-golgi-blockade-of-nascent-desmosomal-cadherins-in-serca2-inhibited-keratinocytes-implications-for-darier-s-disease
#19
Ning Li, Moonhee Park, Shengxiang Xiao, Zhi Liu, Luis A Diaz
Darier's disease (DD) is an autosomal dominantly inherited skin disorder caused by mutations in SERCA2, a Ca(2+) pump that transports Ca(2+) from the cytosol to the endoplasmic reticulum (ER). Loss of desmosomes and keratinocyte cohesion is a characteristic feature of DD. Desmosomal cadherins (DC) are Ca(2+) -dependent transmembrane adhesion proteins of desmosomes, which are mislocalized in the lesional but not perilesional skin of DD. We show here that inhibition of SERCA2 by two distinct inhibitors results in accumulation of DC precursors in keratinocytes, indicating ER-to-Golgi transport of nascent DC is blocked...
February 3, 2017: Traffic
https://www.readbyqxmd.com/read/28154200/pals1-haploinsufficiency-results-in-proteinuria-and-cyst-formation
#20
Thomas Weide, Beate Vollenbröker, Ulf Schulze, Ivona Djuric, Maria Edeling, Jakob Bonse, Florian Hochapfel, Olga Panichkina, Dirk-Oliver Wennmann, Britta George, Seonhee Kim, Christoph Daniel, Jochen Seggewiß, Kerstin Amann, Wilhelm Kriz, Michael P Krahn, Hermann Pavenstädt
The nephron is the basic physiologic subunit of the mammalian kidney and is made up of several apicobasally polarized epithelial cell types. The process of apicobasal polarization in animal cells is controlled by the evolutionarily conserved Crumbs (CRB), Partitioning-defective, and Scribble protein complexes. Here, we investigated the role of protein associated with LIN-7 1 (Pals1, also known as Mpp5), a core component of the apical membrane-determining CRB complex in the nephron. Pals1 interacting proteins, including Crb3 and Wwtr1/Taz, have been linked to renal cyst formation in mice before...
February 2, 2017: Journal of the American Society of Nephrology: JASN
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