Browsing by Subject "GENE"

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  • Nemaline Working Grp; Neuhaus, Sarah B.; Wallgren-Pettersson, Carina; Bönnemann, Carsten G.; Schara, Ulrike; Servais, Laurent (2020)
  • Buettner, Ralf; Le Xuan Truong Nguyen,; Kumar, Bijender; Morales, Corey; Liu, Chao; Chen, Lisa S.; Pemovska, Tea; Synold, Timothy W.; Palmer, Joycelynne; Thompson, Ryan; Li, Ling; Dinh Hoa Hoang,; Zhang, Bin; Ghoda, Lucy; Kowolik, Claudia; Kontro, Mika; Leitch, Calum; Wennerberg, Krister; Yu, Xiaochun; Chen, Ching-Cheng; Horne, David; Gandhi, Varsha; Pullarkat, Vinod; Marcucci, Guido; Rosen, Steven T. (2019)
    Nucleoside analogs represent the backbone of several distinct chemotherapy regimens for acute myeloid leukemia (AML) and combination with tyrosine kinase inhibitors has improved survival of AML patients, including those harboring the poor-risk FLT3-ITD mutation. Although these compounds are effective in killing proliferating blasts, they lack activity against quiescent leukemia stem cells (LSCs), which contributes to initial treatment refractoriness or subsequent disease relapse. The reagent 8-chloro-adenosine (8-Cl-Ado) is a ribose-containing, RNA-directed nucleoside analog that is incorporated into newly transcribed RNA rather than in DNA, causing inhibition of RNA transcription. In this report, we demonstrate antileukemic activities of 8-Cl-Ado in vitro and in vivo and provide mechanistic insight into the mode of action of 8-Cl-Ado in AML. 8-Cl-Ado markedly induced apoptosis in LSC, with negligible effects on normal stem cells. 8-Cl-Ado was particularly effective against AML cell lines and primary AML blast cells harboring the FLT3-ITD mutation. FLT3-ITD is associated with high expression of miR-155. Furthermore, we demonstrate that 8-Cl-Ado inhibits miR-155 expression levels accompanied by induction of DNA-damage and suppression of cell proliferation, through regulation of miR-155/ErbB3 binding protein 1(Ebp1)/p53/PCNA signaling. Finally, we determined that combined treatment of NSG mice engrafted with FLT3-ITD (+) MV4-11 AML cells with 8-Cl-Ado and the FLT3 inhibitor AC220 (quizartinib) synergistically enhanced survival, compared with that of mice treated with the individual drugs, suggesting a potentially effective approach for FLT3-ITD AML patients.
  • Ahonen, Saija J.; Arumilli, Meharji; Lohi, Hannes (2013)
  • Frischknecht, Mirjam; Niehof-Oellers, Helena; Jagannathan, Vidhya; Owczarek-Lipska, Marta; Droegemueller, Cord; Dietschi, Elisabeth; Dolf, Gaudenz; Tellhelm, Bernd; Lang, Johann; Tiira, Katriina; Lohi, Hannes; Leeb, Tosso (2013)
  • Mellor, Nathan; Vaughan-Hirsch, John; Kumpers, Britta M. C.; Help-Rinta-Rahko, Hanna; Miyashima, Shunsuke; Mahonen, Ari Pekka; Campilho, Ana; Kings, John R.; Bishopp, Anthony (2019)
    Pattern formation is typically controlled through the interaction between molecular signals within a given tissue. During early embryonic development, roots of the model plant Arabidopsis thatiana have a radially symmetric pattern, but a heterogeneous input of the hormone auxin from the two cotyledons forces the vascular cylinder to develop a diarch pattern with two xylem poles. Molecular analyses and mathematical approaches have uncovered the regulatory circuit that propagates this initial auxin signal into a stable cellular pattern. The diarch pattern seen in Arabidopsis is relatively uncommon among flowering plants, with most species having between three and eight xylem poles. Here, we have used multiscale mathematical modelling to demonstrate that this regulatory module does not require a heterogeneous auxin input to specify the vascular pattern. Instead, the pattern can emerge dynamically, with its final form dependent upon spatial constraints and growth. The predictions of our simulations compare to experimental observations of xylem pole number across a range of species, as well as in transgenic systems in Arabidopsis in which we manipulate the size of the vascular cylinder. By considering the spatial constraints, our model is able to explain much of the diversity seen in different flowering plant species.
  • Mollerup, Filip; Aumala, Ville; Parikka, Kirsti Maria; Mathieu, Yan; Brumer, Harry; Tenkanen, Tiina Maija; Master, Emma (2019)
    Copper radical alcohol oxidases belonging to auxiliary activity family 5, subfamily 2 (AA5_2) catalyze the oxidation of galactose and galactosides, as well as aliphatic alcohols. Despite their broad applied potential, so far very few AA5_2 members have been biochemically characterized. We report the recombinant production and biochemical characterization of an AA5_2 oxidase from Penicillium rubens Wisconsin 54-1255 (PruAA5_2A), which groups within an unmapped clade phylogenetically distant from those comprising AA5_2 members characterized to date. PruAA5_2 preferentially oxidized raffinose over galactose; however, its catalytic efficiency was 6.5 times higher on glycolaldehyde dimer compared to raffinose. Deep sequence analysis of characterized AA5_2 members highlighted amino acid pairs correlated to substrate range and conserved within the family. Moreover, PruAA5_2 activity spans substrate preferences previously reported for AA5 subfamily 1 and 2 members, identifying possible functional overlap across the AA5 family.
  • Jylhava, Juulia; Lyytikainen, Leo-Pekka; Kahonen, Mika; Hutri-Kahonen, Nina; Kettunen, Johannes; Viikari, Jorma; Raitakari, Olli T.; Lehtimaki, Terho; Hurme, Mikko (2012)
  • Surakka, Ida; Isaacs, Aaron; Karssen, Lennart C.; Laurila, Pirkka-Pekka P.; Middelberg, Rita P. S.; Tikkanen, Emmi; Ried, Janina S.; Lamina, Claudia; Mangino, Massimo; Igl, Wilmar; Hottenga, Jouke-Jan; Lagou, Vasiliki; van der Harst, Pim; Leach, Irene Mateo; Esko, Tonu; Kutalik, Zoltan; Wainwright, Nicholas W.; Struchalin, Maksim V.; Sarin, Antti-Pekka; Kangas, Antti J.; Viikari, Jorma S.; Perola, Markus; Rantanen, Taina; Petersen, Ann-Kristin; Soininen, Pasi; Johansson, Asa; Soranzo, Nicole; Heath, Andrew C.; Papamarkou, Theodore; Prokopenko, Inga; Toenjes, Anke; Kronenberg, Florian; Doering, Angela; Rivadeneira, Fernando; Montgomery, Grant W.; Whitfield, John B.; Kahonen, Mika; Lehtimaki, Terho; Freimer, Nelson B.; Willemsen, Gonneke; de Geus, Eco J. C.; Palotie, Aarno; Sandhu, Manj S.; Waterworth, Dawn M.; Metspalu, Andres; Stumvoll, Michael; Uitterlinden, Andre G.; Jula, Antti; Navis, Gerjan; Wijmenga, Cisca; Wolffenbuttel, Bruce H. R.; Taskinen, Marja-Riitta; Ala-Korpela, Mika; Kaprio, Jaakko; Kyvik, Kirsten O.; Boomsma, Dorret I.; Pedersen, Nancy L.; Gyllensten, Ulf; Wilson, James F.; Rudan, Igor; Campbell, Harry; Pramstaller, Peter P.; Spector, Tim D.; Witteman, Jacqueline C. M.; Eriksson, Johan G.; Salomaa, Veikko; Oostra, Ben A.; Raitakari, Olli T.; Wichmann, H. -Erich; Gieger, Christian; Jaervelin, Marjo-Riitta; Martin, Nicholas G.; Hofman, Albert; McCarthy, Mark I.; Palotie, Leena; van Duijn, Cornelia M.; Aulchenko, Yurii S.; Ripatti, Samuli (2011)
  • Drug-Induced Liver Injury Network; Int DILI Consortium iDILIC; Cirulli, Elizabeth T.; Nicoletti, Paola; Laitinen, Tarja (2019)
    BACKGROUND & AIMS: We performed genetic analyses of a multiethnic cohort of patients with idiosyncratic drug-induced liver injury (DILI) to identify variants associated with susceptibility. METHODS: We performed a genome-wide association study of 2048 individuals with DILI (cases) and 12,429 individuals without (controls). Our analysis included subjects of European (1806 cases and 10,397 controls), African American (133 cases and 1,314 controls), and Hispanic (109 cases and 718 controls) ancestry. We analyzed DNA from 113 Icelandic cases and 239,304 controls to validate our findings. RESULTS: We associated idiosyncratic DILI with rs2476601, a nonsynonymous polymorphism that encodes a substitution of tryptophan with arginine in the protein tyrosine phosphatase, nonreceptor type 22 gene (PTPN22) (odds ratio [OR] 1.44; 95% confidence interval [CI] 1.28-1.62; P = 1.2 x 10(-9) and replicated the finding in the validation set (OR 1.48; 95% CI 1.09-1.99; P =.01). The minor allele frequency showed the same effect size (OR > 1) among ethnic groups. The strongest association was with amoxicillin and clavulanate-associated DILI in persons of European ancestry (OR 1.62; 95% CI 1.32-1.98; P = 4.0 x 10(-6); allele frequency = 13.3%), but the polymorphism was associated with DILI of other causes (OR 1.37; 95% CI 1.21-1.56; P = 1.5 x 10(-6); allele frequency = 11.5%). Among amoxicillin-and clavulanate-associated cases of European ancestry, rs2476601 doubled the risk for DILI among those with the HLA risk alleles A* 02: 01 and DRB1* 15: 01. CONCLUSIONS: In a genome-wide association study, we identified rs2476601 in PTPN22 as a non-HLA variant that associates with risk of liver injury caused by multiple drugs and validated our finding in a separate cohort. This variant has been associated with increased risk of autoimmune diseases, providing support for the concept that alterations in immune regulation contribute to idiosyncratic DILI.
  • JSCRG; TSRHCCG (2018)
    Adolescent idiopathic scoliosis (AIS) is the most common type of spinal deformity and has a significant genetic background. Genome-wide association studies (GWASs) identified several susceptibility loci associated with AIS. Among them is a locus on chromosome 6q24.1 that we identified by a GWAS in a Japanese cohort. The locus is represented by rs6570507 located within GPR126. To ensure the association of rs6570507 with AIS, we conducted a meta-analysis using eight cohorts from East Asia, Northern Europe and USA. The analysis included a total of 6,873 cases and 38,916 controls and yielded significant association (combined P = 2.95 x 10(-20); odds ratio = 1.22), providing convincing evidence of the worldwide association between rs6570507 and AIS susceptibility. In silico analyses strongly suggested that GPR126 is a susceptibility gene at this locus.
  • Ryhänen, Eeva; Leijon, Helena; Metso, Saara; Eloranta, Eija; Korsoff, Pirkko; Ahtiainen, Petteri; Kekäläinen, Päivi; Tamminen, Marjo; Ristamaki, Raija; Knutar, Otto; Loyttyniemi, Eliisa; Niskanen, Leo; Väisänen, Mika; Heiskanen, Ilkka Sten; Välimäki, Matti; Laakso, Markku; Haglund, Caj; Arola, Johanna; Schalin-Jantti, Camilla (2017)
    Background: Parathyroid carcinoma (PC) is rare and diagnostically challenging. Reported outcomes are rather poor and the incidence might be increasing.Material and methods: We performed a nationwide study on all cases (n=32) diagnosed in 2000-2011 in Finland, and compared clinical and histopathological characteristics and outcome to atypical parathyroid (APA; n=28) and parathyroid adenomas (PA; n=72). The incidence in years 1955-1999 was compared to that in 2000-2013.Results: Preoperatively, calcium and parathyroid hormone concentrations were higher in PC compared to APA and PA (1.76, 1.56 and 1.44mmol/l, p
  • Escala-Garcia, M.; Abraham, J.; Andrulis, I.L.; Anton-Culver, H.; Arndt, V.; Ashworth, A.; Auer, P.L.; Auvinen, P.; Beckmann, M.W.; Beesley, J.; Behrens, S.; Benitez, J.; Bermisheva, M.; Blomqvist, C.; Blot, W.; Bogdanova, N.V.; Bojesen, S.E.; Bolla, M.K.; Børresen-Dale, A.-L.; Brauch, H.; Brenner, H.; Brucker, S.Y.; Burwinkel, B.; Caldas, C.; Canzian, F.; Chang-Claude, J.; Chanock, S.J.; Chin, S.-F.; Clarke, C.L.; Couch, F.J.; Cox, A.; Cross, S.S.; Czene, K.; Daly, M.B.; Dennis, J.; Devilee, P.; Dunn, J.A.; Dunning, A.M.; Dwek, M.; Earl, H.M.; Eccles, D.M.; Eliassen, A.H.; Ellberg, C.; Evans, D.G.; Fasching, P.A.; Figueroa, J.; Flyger, H.; Gago-Dominguez, M.; Gapstur, S.M.; García-Closas, M.; García-Sáenz, J.A.; Gaudet, M.M.; George, A.; Giles, G.G.; Goldgar, D.E.; González-Neira, A.; Grip, M.; Guénel, P.; Guo, Q.; Haiman, C.A.; Håkansson, N.; Hamann, U.; Harrington, P.A.; Hiller, L.; Hooning, M.J.; Hopper, J.L.; Howell, A.; Huang, C.-S.; Huang, G.; Hunter, D.J.; Jakubowska, A.; John, E.M.; Kaaks, R.; Kapoor, P.M.; Keeman, R.; Kitahara, C.M.; Koppert, L.B.; Kraft, P.; Kristensen, V.N.; Lambrechts, D.; Le Marchand, L.; Lejbkowicz, F.; Lindblom, A.; Lubiński, J.; Mannermaa, A.; Manoochehri, M.; Manoukian, S.; Margolin, S.; Martinez, M.E.; Maurer, T.; Mavroudis, D.; Meindl, A.; Milne, R.L.; Mulligan, A.M.; Neuhausen, S.L.; Nevanlinna, H.; Newman, W.G.; Olshan, A.F.; Olson, J.E.; Olsson, H.; Orr, N.; Peterlongo, P.; Petridis, C.; Prentice, R.L.; Presneau, N.; Punie, K.; Ramachandran, D.; Rennert, G.; Romero, A.; Sachchithananthan, M.; Saloustros, E.; Sawyer, E.J.; Schmutzler, R.K.; Schwentner, L.; Scott, C.; Simard, J.; Sohn, C.; Southey, M.C.; Swerdlow, A.J.; Tamimi, R.M.; Tapper, W.J.; Teixeira, M.R.; Terry, M.B.; Thorne, H.; Tollenaar, R.A.E.M.; Tomlinson, I.; Troester, M.A.; Truong, T.; Turnbull, C.; Vachon, C.M.; van der Kolk, L.E.; Wang, Q.; Winqvist, R.; Wolk, A.; Yang, X.R.; Ziogas, A.; Pharoah, P.D.P.; Hall, P.; Wessels, L.F.A.; Chenevix-Trench, G.; Bader, G.D.; Dörk, T.; Easton, D.F.; Canisius, S.; Schmidt, M.K. (2020)
    Identifying the underlying genetic drivers of the heritability of breast cancer prognosis remains elusive. We adapt a network-based approach to handle underpowered complex datasets to provide new insights into the potential function of germline variants in breast cancer prognosis. This network-based analysis studies similar to 7.3 million variants in 84,457 breast cancer patients in relation to breast cancer survival and confirms the results on 12,381 independent patients. Aggregating the prognostic effects of genetic variants across multiple genes, we identify four gene modules associated with survival in estrogen receptor (ER)-negative and one in ER-positive disease. The modules show biological enrichment for cancer-related processes such as G-alpha signaling, circadian clock, angiogenesis, and Rho-GTPases in apoptosis.
  • van der Valk, Ralf J. P.; Kreiner-Moller, Eskil; Kooijman, Marjolein N.; Guxens, Monica; Stergiakouli, Evangelia; Saaf, Annika; Bradfield, Jonathan P.; Geller, Frank; Hayes, M. Geoffrey; Cousminer, Diana L.; Koerner, Antje; Thiering, Elisabeth; Curtin, John A.; Myhre, Ronny; Huikari, Ville; Joro, Raimo; Kerkhof, Marjan; Warrington, Nicole M.; Pitkanen, Niina; Ntalla, Ioanna; Horikoshi, Momoko; Veijola, Riitta; Freathy, Rachel M.; Teo, Yik-Ying; Barton, Sheila J.; Evans, David M.; Kemp, John P.; St Pourcain, Beate; Ring, Susan M.; Smith, George Davey; Bergstrom, Anna; Kull, Inger; Hakonarson, Hakon; Mentch, Frank D.; Bisgaard, Hans; Chawes, Bo; Stokholm, Jakob; Waage, Johannes; Eriksen, Patrick; Sevelsted, Astrid; Melbye, Mads; van Duijn, Cornelia M.; Medina-Gomez, Carolina; Hofman, Albert; de Jongste, Johan C.; Taal, H. Rob; Eriksson, Johan; Palotie, Aarno; Knip, Mikael; Widen, Elisabeth; Early Genetics Lifecourse; Genetic Invest ANthropometric; Early Growth Genetics EGG (2015)
  • Kausar, Mehran; Chew, Elaine Guo Yan; Ullah, Hazrat; Anees, Mariam; Khor, Chiea Chuen; Foo, Ia Nee; Makitie, Outi; Siddiqi, Saima (2019)
    We report on three new patients with spondyloocular syndrome (SOS) in a consanguineous Pakistani family. All three patients present progressive generalized osteoporosis, short stature, recurrent fractures, hearing loss and visual impairments. WES revealed a novel homozygous frameshift variant in exon 11 of XYLT2 (NG 012175.1, NP_071450.2) resulting in loss of evolutionary conserved amino acid sequences (840 - 865/865) at C -terminus p.R840fs*115. Sanger Sequencing confirmed the presence of the novel homozygous mutation in all three patients while the parents were heterozygous carriers of the mutation, in accordance with an autosomal recessive inheritance pattern. Only nine variants worldwide have previously been reported in XYLT2 in patients with SOS phenotype. These three patients with novel homozygous variant extend the genotypic and phenotypic spectrum of SOS.
  • Kuuluvainen, Liina; Pöyhönen, Minna; Pasanen, Petra; Siitonen, Maija; Rummukainen, Jaana; Tienari, Pentti J.; Paetau, Anders; Myllykangas, Liisa (2017)
    Mutations in the progranulin (GRN) gene represent about 5-10% of frontotemporal lobar degeneration (FTLD). We describe a proband with a novel GRN mutation c.687T>A, p.(Tyr229*), presenting with dyspraxia, dysgraphia, and dysphasia at the age of 60 and a very severe FTLD neuropathological phenotype with TDP43 inclusions. The nephew of the proband had signs of dementia and personality changes at the age of 60 and showed similar but milder FTLD pathology. Three other family members had had early-onset dementia. Gene expression studies showed decreased GRN gene expression in mutation carriers' blood samples. In conclusion, we describe a novel GRN, p.(Tyr229*) mutation, resulting in haploinsufficiency of GRN and a severe neuropathologic FTLD phenotype.
  • Jackson, C. B.; Bauer, M. F.; Schaller, A.; Kotzaeridou, U.; Ferrarini, A.; Hahn, D.; Chehade, H.; Barbey, F.; Tran, C.; Gallati, S.; Haeberli, A.; Eggimann, S.; Bonafe, L.; Nuoffer, J-M. (2016)
    We report a novel homozygous missense mutation in the ubiquinol-cytochrome c reductase synthesis-like (BCS1L) gene in two consanguineous Turkish families associated with deafness, Fanconi syndrome (tubulopathy), microcephaly, mental and growth retardation. All three patients presented with transitory metabolic acidosis in the neonatal period and development of persistent renal de Toni-Debr,-Fanconi-type tubulopathy, with subsequent rachitis, short stature, microcephaly, sensorineural hearing impairment, mild mental retardation and liver dysfunction. The novel missense mutation c.142A > G (p.M48V) in BCS1L is located at a highly conserved region associated with sorting to the mitochondria. Biochemical analysis revealed an isolated complex III deficiency in skeletal muscle not detected in fibroblasts. Native polyacrylamide gel electrophoresis (PAGE) revealed normal super complex formation, but a shift in mobility of complex III most likely caused by the absence of the BCS1L-mediated insertion of Rieske Fe/S protein into complex III. These findings expand the phenotypic spectrum of BCS1L mutations, highlight the importance of biochemical analysis of different primary affected tissue and underline that neonatal lactic acidosis with multi-organ involvement may resolve after the newborn period with a relatively spared neurological outcome and survival into adulthood. Conclusion: Mutation screening for BCS1L should be considered in the differential diagnosis of severe (proximal) tubulopathy in the newborn period.
  • Flisikowski, Krzysztof; Venhoranta, Heli; Nowacka-Woszuk, Joanna; McKay, Stephanie D.; Flyckt, Antti; Taponen, Juhani; Schnabel, Robert; Schwarzenbacher, Hermann; Szczerbal, Izabela; Lohi, Hannes; Fries, Ruedi; Taylor, Jeremy F.; Switonski, Marek; Andersson, Magnus (2010)
  • Loid, Petra; Mäkitie, Riikka; Costantini, Alice; Viljakainen, Heli; Pekkinen, Minna; Mäkitie, Outi (2018)
    The genetic background of severe early-onset obesity is still incompletely understood. Deletions at 2p25.3 associate with early-onset obesity and variable intellectual disability. Myelin-transcriptor-factor-1-like (MYT1L) gene in this locus has been proposed a candidate gene for obesity. We report on a 13-year-old boy presenting with overweight already at 1 year of age (body mass index [BMI] Z-score +2.3) and obesity at 2 years of age (BMI Z-score +3.8). The patient had hyperphagia and delayed neurological, cognitive and motor development. He also had speech delay, strabismus, hyperactivity and intellectual disability. Brain MRI was normal. The parents and sister had normal BMI. Whole-genome sequencing identified in the index patient a novel de novo frameshift deletion that introduces a premature termination of translation NM_015025.2(MYT1L): c.2215_2224delACGCGCTGCC, p.(Thr739Alafs*7) in MYT1L. The frameshift variant was confirmed by Sanger sequencing. Our finding supports the association of MYT1L mutations with early-onset syndromic obesity. The identification of novel monogenic forms of childhood-onset obesity will provide insights to the involved genetic and biologic pathways.
  • Silventoinen, Karri; Volanen, Salla-Maarit; Vuoksimaa, Eero; Rose, Richard J.; Suominen, Sakari; Kaprio, Jaakko (2014)