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Raffaella Sordella, Nitin H Shirole, Debjani Pal, Edward R Kastenhuber, Serif Senturk, Joseph Boroda, Paola Pisterzi, Madison Miller, Gustavo Munoz, Marko Anderluh, Marc Ladanyi, Scott W Lowe
TP53 truncating mutations are common in human tumors and are thought to give rise to p53-null alleles. Here, we show that TP53 exon-6 truncating mutations occur at higher than expected frequencies and produce proteins that lack canonical p53 tumor suppressor activities but promote cancer cell proliferation, survival, and metastasis. Functionally and molecularly, these p53 mutants resemble the naturally occurring alternative p53 splice variant, p53-psi. Accordingly, these mutants can localize to mitochondria where they promote tumor phenotypes by binding and activating the mitochondria inner pore permeability regulator, Cyclophilin D (CypD)...
October 19, 2016: ELife
Daniel Nava Rodrigues, Gunther Boysen, Semini Sumanasuriya, George Seed, Angelo M De Marzo, Johann de Bono
Prostate cancer (PCa) is a clinically heterogeneous disease and current treatment strategies are based largely on anatomical and pathological parameters. In the recent past, several DNA sequencing studies of primary and advanced PCa have revealed recurrent patterns of genomic aberrations that expose mechanisms of resistance to available therapies and potential new drug targets. Suppression of androgen receptor (AR) signalling is the cornerstone of advanced prostate cancer treatment. Genomic aberrations of the androgen receptor or alternative splicing of its mRNA are increasingly recognized as biomarkers of resistance to AR-targeted therapy such as abiraterone or enzalutamide...
October 18, 2016: Journal of Pathology
O Sakiragaoglu, A L Munn
To inhibit telomerase activity, a construct which contains artificial introns in the enhanced green fluorescent protein (EGFP) gene that encodes small hairpin RNA (shRNA) sequences that target human telomerase reverse transcriptase (hTERT) gene expression was designed and tested for its effect on lung cancer cell line. On intron splicing from the construct, intronic sequences were released and formed shRNA in the cells. After transfection of the construct, hTERT mRNA expression decreased by approximately 55 % in A549 cells...
October 17, 2016: Molecular Biotechnology
He Wang, Yanmei Chen, Xinzhong Li, Guojun Chen, Lintao Zhong, Gangbing Chen, Yulin Liao, Wangjun Liao, Jianping Bin
Alternative splicing (AS) drives determinative changes during mouse heart development. Recent high-throughput technological advancements have facilitated genome-wide AS, while its analysis in human foetal heart transition to the adult stage has not been reported. Here, we present a high-resolution global analysis of AS transitions between human foetal and adult hearts. RNA-sequencing data showed extensive AS transitions occurred between human foetal and adult hearts, and AS events occurred more frequently in protein-coding genes than in long non-coding RNA (lncRNA)...
October 18, 2016: Scientific Reports
Christina R Tyler, Matthew T Labrecque, Elizabeth R Solomon, Xun Guo, Andrea M Allan
Exposure to arsenic, a common environmental toxin found in drinking water, leads to a host of neurological pathologies. We have previously demonstrated that developmental exposure to a low level of arsenic (50ppb) alters epigenetic processes that underlie deficits in adult hippocampal neurogenesis leading to aberrant behavior. It is unclear if arsenic impacts the programming and regulation of embryonic neurogenesis during development when exposure occurs. The master negative regulator of neural-lineage, REST/NRSF, controls the precise timing of fate specification and differentiation of neural stem cells (NSCs)...
October 14, 2016: Neurotoxicology and Teratology
Fernanda Sales Luiz Vianna, Thayne Woycinck Kowalski, Luciana Tovo-Rodrigues, Alice Tagliani-Ribeiro, Bibiane Armiliato Godoy, Lucas Rosa Fraga, Maria Teresa Vieira Sanseverino, Mara Helena Hutz, Lavínia Schuler-Faccini
Thalidomide causes Thalidomide Embryopathy (TE), but is largely used to treat several conditions. Investigations with Cereblon, a thalidomide target protein encoded by CRBN gene, have helped to understand thalidomide therapeutic and teratogenic properties. We sequenced CRBN-thalidomide binding region in 38 TE individuals and 136 Brazilians without congenital anomalies, and performed in silico analyses. Eight variants were identified, seven intronic and one in 3'UTR. TE individuals had rare variants in higher frequency than the non-affected group(p=0...
October 14, 2016: Reproductive Toxicology
David S Lynch, Wei Jia Zhang, Rahul Lakshmanan, Justin A Kinsella, Günes Altiokka Uzun, Merih Karbay, Zeynep Tüfekçioglu, Hasmet Hanagasi, Georgina Burke, Nicola Foulds, Simon R Hammans, Anupam Bhattacharjee, Heather Wilson, Matthew Adams, Mark Walker, James A R Nicoll, Jeremy Chataway, Nick Fox, Indran Davagnanam, Rahul Phadke, Henry Houlden
Importance: Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) is a frequent cause of adult-onset leukodystrophy known to be caused by autosomal dominant mutations in the CSF1R (colony-stimulating factor 1) gene. The discovery that CSF1R mutations cause ALSP led to more accurate prognosis and genetic counseling for these patients in addition to increased interest in microglia as a target in neurodegeneration. However, it has been known since the discovery of the CSF1R gene that there are patients with typical clinical and radiologic evidence of ALSP who do not carry pathogenic CSF1R mutations...
October 17, 2016: JAMA Neurology
Zachery R Reichert, Maha Hussain
The development of metastatic castration-resistant prostate cancer (mCRPC) signals the terminal disease phase. The preceding hormone-dependent disease setting is effectively managed with androgen deprivation therapy. This foundation of treatment has a high rate of biochemical and clinical response and meaningful clinical benefit but is finite in duration as most cancers will progress to castration resistance. Historically, treatment for mCRPC entailed androgen receptor (AR) inhibitors (nilutamide, flutamide, bicalutamide), nonspecific steroidal biosynthesis inhibitors (ketoconazole, itraconazole), steroids (prednisone, diethylstilbesterol, dexamethasone), or palliative chemotherapy (mitoxantrone, estramustine), but none of these strategies impacted survival...
September 2016: Cancer Journal
Michael Saul, Petra Majdak, Samuel Perez, Matthew Reilly, Theodore Garland, Justin S Rhodes
Though exercise is critical for health, many lack the motivation to exercise, and it is unclear how motivation might be increased. To uncover the molecular underpinnings of increased motivation for exercise, we analyzed the transcriptome of the striatum in four mouse lines selectively bred for high voluntary wheel running and four non-selected control lines. The striatum was dissected and RNA was extracted and sequenced from four individuals of each line. We found multiple genes and gene systems with strong relationships to both selection and running history over the previous 6 days...
October 17, 2016: Genes, Brain, and Behavior
Xiao-Jun Chen, Hong Zhang, Zhi-Ping Tan, Wen Hu, Yi-Feng Yang
Multiple osteochondromas (MO), also known as hereditary multiple exostoses, is an autosomal dominant bone disorder. Mutations in exostosin glycosyl transferase‑1 (EXT1) and exostosin glycosyl transferase‑2 (EXT2), including missense, nonsense, frameshift and splice‑site mutations, account for up to 80% of reported cases. The proteins EXT1 and EXT2 form a hetero‑oligomeric complex that functions in heparan sulfate proteoglycan biosynthesis. A heterozygous EXT2 mutation, c.939+1G>T, was identified in a five‑generation 33‑member MO family, and was present in all 13 affected members...
October 6, 2016: Molecular Medicine Reports
Jiali Li, Xueshan Xiao, Shiqiang Li, Xiaoyun Jia, Xiangming Guo, Qingjiong Zhang
It has been previously reported that mutations in retinal G protein coupled receptor (RGR) are associated with retinitis pigmentosa. The present study aims to systemically analyze the potential role of variants of RGR in retinal diseases. Variants in coding regions and splice sites of RGR were selected from a whole exome sequencing dataset of 820 probands with various forms of genetic ocular diseases. Potential variants of RGR were further confirmed by Sanger sequencing and analyzed in available family members...
October 13, 2016: Molecular Medicine Reports
Hiroki Otsuka, Hideo Sasai, Mina Nakama, Yuka Aoyama, Elsayed Abdelkreem, Hidenori Ohnishi, Vassiliki Konstantopoulou, Jörn Oliver Sass, Toshiyuki Fukao
Beta-ketothiolase deficiency, also known as mitochondrial acetoacetyl-CoA thiolase (T2) deficiency, is an autosomal recessive disease caused by mutations in the acetyl‑CoA acetyltransferase 1 (ACAT1) gene. A German T2‑deficient patient that developed a severe ketoacidotic episode at the age of 11 months, was revealed to be a compound heterozygote of a previously reported null mutation, c.472A>G (p.N158D) and a novel mutation, c.949G>A (p.D317N), in ACAT1. The c.949G>A mutation was suspected to cause aberrant splicing as it is located within an exonic splicing enhancer sequence (c...
October 10, 2016: Molecular Medicine Reports
Hao Zhang, Hua Yue, Chun Wang, Weiwei Hu, Jiemei Gu, Jinwei He, Wenzhen Fu, Yunqiu Hu, Miao Li, Zhenlin Zhang
Osteogenesis imperfecta (OI) is an inherited connective tissue disorder characterized by brittle bone fractures. The aim of the present study was to investigate the pathogenic gene mutation spectrum and clinical manifestations of mutations in collagen type I, alpha 1 (COL1A1) and collagen type I, alpha 2 (COL1A2) genes in Chinese patients with OI. A total of 61 unrelated Chinese OI patients with COL1A1 and COL1A2 mutations were recruited. All the exons and the exon-intron boundaries of the COL1A1 and COL1A2 genes were amplified and directly sequenced and lumbar spine bone mineral density was measured by dual‑energy X‑ray absorptiometry...
October 12, 2016: Molecular Medicine Reports
Rachael L Cohen, Russell L Margolis
PURPOSE OF REVIEW: Spinocerebellar ataxia type 12 (SCA12) is a rare autosomal dominant neurodegenerative disease characterized by tremor, gait abnormalities, and neuropsychiatric syndromes. The location of the causative CAG/CTG expansion mutation in PPP2R2B, a gene encoding regulatory units of the protein phosphatase 2A, may provide unique insights into the pathogenesis of neurodegeneration. RECENT FINDINGS: The first neuropathological examination of a brain from an SCA12 patient revealed both cerebellar and cerebral cortical atrophy, with a noted loss of Purkinje cells and no evidence of polyglutamine aggregates...
September 29, 2016: Current Opinion in Neurology
Madeleine Berger, Alin Mirel Puinean, Emma Randall, Christoph T Zimmer, Wellington M Silva, Pablo Bielza, Linda M Field, David Hughes, Ian Mellor, Keywan Hassani-Pak, Herbert A A Siqueira, Martin S Williamson, Chris Bass
Many genes increase coding capacity by alternate exon usage. The gene encoding the insect nicotinic acetylcholine receptor (nAChR) α6 subunit, target of the bio-insecticide spinosad, is one example of this and expands protein diversity via alternative splicing of mutually exclusive exons. Here we show that spinosad resistance in the tomato leafminer, Tuta absoluta is associated with aberrant regulation of splicing of Taα6 resulting in a novel form of insecticide resistance mediated by exon skipping. Sequencing of the α6 subunit cDNA from spinosad selected and unselected strains of T...
October 17, 2016: Molecular Ecology
Michele Balsamo, Chandrani Mondal, Guillaume Carmona, Leslie M McClain, Daisy N Riquelme, Jenny Tadros, Duan Ma, Eliza Vasile, John S Condeelis, Douglas A Lauffenburger, Frank B Gertler
During tumor progression, alternative splicing gives rise to different Mena protein isoforms. We analyzed how Mena11a, an isoform enriched in epithelia and epithelial-like cells, affects Mena-dependent regulation of actin dynamics and cell behavior. While other Mena isoforms promote actin polymerization and drive membrane protrusion, we find that Mena11a decreases actin polymerization and growth factor-stimulated membrane protrusion at lamellipodia. Ectopic Mena11a expression slows mesenchymal-like cell motility, while isoform-specific depletion of endogenous Mena11a in epithelial-like tumor cells perturbs cell:cell junctions and increases membrane protrusion and overall cell motility...
October 17, 2016: Scientific Reports
John G Conboy
The Rbfox genes encode an ancient family of sequence-specific RNA binding proteins (RBPs) that are critical developmental regulators in multiple tissues including skeletal muscle, cardiac muscle, and brain. The hallmark of Rbfox proteins is a single high-affinity RRM domain, highly conserved from insects to humans, that binds preferentially to UGCAUG motifs at diverse regulatory sites in pre-mRNA introns, mRNA 3'UTRs, and pre-miRNAs hairpin structures. Versatile regulatory circuits operate on Rbfox pre-mRNA and mRNA to ensure proper expression of Rbfox1 protein isoforms, which then act on the broader transcriptome to regulate alternative splicing networks, mRNA stability and translation, and microRNA processing...
October 17, 2016: Wiley Interdisciplinary Reviews. RNA
Tasuku Suzuki, Yoji Sasahara, Atsuo Kikuchi, Humihiko Kakuta, Toshihiko Kashiwabara, Takashi Ishige, Yoshiko Nakayama, Masanori Tanaka, Akihiro Hoshino, Hirokazu Kanegane, Daiki Abukawa, Shigeo Kure
PURPOSE: Pediatric inflammatory bowel disease (IBD) is a heterogeneous disorder caused by multiple factors. Although genetic and immunological analyses are required for a definitive diagnosis, no reports of a comprehensive genetic study of a Japanese population are available. METHODS: In total, 35 Japanese patients <16 years of age suffering from IBD, including 27 patients aged <6 years with very early-onset IBD, were enrolled in this multicenter study. Exome and targeted gene panel sequencing was performed for all patients...
October 17, 2016: Journal of Clinical Immunology
Alessandra Ruggieri, Simona Saredi, Simona Zanotti, Maria Barbara Pasanisi, Lorenzo Maggi, Marina Mora
Mutations in the DNAJB6 gene have been associated with the autosomal dominant limb girdle muscular dystrophy type 1D (LGMD1D), a disorder characterized by abnormal protein aggregates and rimmed vacuoles in muscle fibers. DNAJB6 is a ubiquitously expressed Hsp40 co-chaperone characterized by a J domain that specifies Hsp70 functions in the cellular environment. DNAJB6 is also a potent inhibitor of expanded polyglutamine (polyQ) aggregation preventing aggregate toxicity in cells. In DNAJB6-mutated patients this anti-aggregation property is significantly reduced, albeit not completely lost...
2016: Frontiers in Molecular Biosciences
Josh Clevenger, Ye Chu, Brian Scheffler, Peggy Ozias-Akins
The advent of the genome sequences of Arachis duranensis and Arachis ipaensis has ushered in a new era for peanut genomics. With the goal of producing a gene atlas for cultivated peanut (Arachis hypogaea), 22 different tissue types and ontogenies that represent the full development of peanut were sequenced, including a complete reproductive series from flower to peg elongation and peg tip immersion in the soil to fully mature seed. Using a genome-guided assembly pipeline, a homeolog-specific transcriptome assembly for Arachis hypogaea was assembled and its accuracy was validated...
2016: Frontiers in Plant Science
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