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  • 1. Abel, Olubunmi
    et al.
    Powell, John F.
    Andersen, Peter M.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Al-Chalabi, Ammar
    ALSoD: A user-friendly online bioinformatics tool for amyotrophic lateral sclerosis genetics2012In: Human Mutation, ISSN 1059-7794, E-ISSN 1098-1004, Vol. 33, no 9, p. 1345-1351Article in journal (Refereed)
    Abstract [en]

    Amyotrophic lateral sclerosis (ALS) is the commonest adult onset motor neuron disease, with a peak age of onset in the seventh decade. With advances in genetic technology, there is an enormous increase in the volume of genetic data produced, and a corresponding need for storage, analysis, and interpretation, particularly as our understanding of the relationships between genotype and phenotype mature. Here, we present a system to enable this in the form of the ALS Online Database (ALSoD at http://alsod.iop.kcl.ac.uk), a freely available database that has been transformed from a single gene storage facility recording mutations in the SOD1 gene to a multigene ALS bioinformatics repository and analytical instrument combining genotype, phenotype, and geographical information with associated analysis tools. These include a comparison tool to evaluate genes side by side or jointly with user configurable features, a pathogenicity prediction tool using a combination of computational approaches to distinguish variants with nonfunctional characteristics from disease-associated mutations with more dangerous consequences, and a credibility tool to enable ALS researchers to objectively assess the evidence for gene causation in ALS. Furthermore, integration of external tools, systems for feedback, annotation by users, and two-way links to collaborators hosting complementary databases further enhance the functionality of ALSoD. Hum Mutat 33:1345-1351, 2012. (c) 2012 Wiley Periodicals, Inc.

  • 2. Blasco, Helene
    et al.
    Bernard-Marissal, Nathalie
    Vourc'h, Patrick
    Guettard, Yves Olivier
    Sunyach, Claire
    Augereau, Olivier
    Khederchah, Joelle
    Mouzat, Kevin
    Antar, Catherine
    Gordon, Paul H.
    Veyrat-Durebex, Charlotte
    Besson, Gerard
    Andersen, Peter M.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Salachas, Francois
    Meininger, Vincent
    Camu, William
    Pettmann, Brigitte
    Andres, Christian R.
    Corcia, Philippe
    A Rare Motor Neuron Deleterious Missense Mutation in the DPYSL3 (CRMP4) Gene is Associated with ALS2013In: Human Mutation, ISSN 1059-7794, E-ISSN 1098-1004, Vol. 34, no 7, p. 953-960Article in journal (Refereed)
    Abstract [en]

    The dihydropyrimidinase-like 3 (DPYSL3) or Collapsin Response Mediator Protein 4a (CRMP4a) expression is modified in neurodegeneration and is involved in several ALS-associated pathways including axonal transport, glutamate excitotoxicity, and oxidative stress. The objective of the study was to analyze CRMP4 as a risk factor for ALS. We analyzed the DPYSL3/CRMP4 gene in French ALS patients (n=468) and matched-controls (n=394). We subsequently examined a variant in a Swedish population (184 SALS, 186 controls), and evaluated its functional effects on axonal growth and survival in motor neuron cell culture. The rs147541241:A>G missense mutation occurred in higher frequency among French ALS patients (odds ratio=2.99) but the association was not confirmed in the Swedish population. In vitro expression of mutated DPYSL3 in motor neurons reduced axonal growth and accelerated cell death compared with wild type protein. Thus, the association between the rs147541241 variant and ALS was limited to the French population, highlighting the geographic particularities of genetic influences (risks, contributors). The identified variant appears to shorten motor neuron survival through a detrimental effect on axonal growth and CRMP4 could act as a key unifier in transduction pathways leading to neurodegeneration through effects on early axon development.

  • 3. Borg, Kristian
    et al.
    Stucka, Rolf
    Locke, Matthew
    Melin, Eva
    Ahlberg, Gabrielle
    Klutzny, Ursula
    Hagen, Maja von der
    Huebner, Angela
    Lochmüller, Hanns
    Wrogemann, Klaus
    Thornell, Lars-Eric
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Blake, Derek J
    Schoser, Benedikt
    Intragenic deletion of TRIM32 in compound heterozygotes with sarcotubular myopathy/LGMD2H2009In: Human Mutation, ISSN 1059-7794, E-ISSN 1098-1004, Vol. 30, no 9, p. E831-E844Article in journal (Refereed)
    Abstract [en]

    In 2005 the commonality of sarcotubular myopathy (STM) and limb girdle muscular dystrophy type 2H (LGMD2H) was demonstrated, as both are caused by the p D487N missense mutation in TRIM32 originally found in the Manitoba Hutterite population. Recently, three novel homozygous TRIM32 mutations have been described in LGMD patients. Here we describe a three generation Swedish family clinically presenting with limb girdle muscular weakness and histological features of a microvacuolar myopathy. The two index patients were compound heterozygotes for a frameshift mutation in TRIM32 (c.1560delC ) and a 30 kb intragenic deletion, encompassing parts of intron 1 and the entire exon 2 of TRIM32. In these patients, no full-length or truncated TRIM32 could be detected. Interestingly, heterozygous family members carrying only one mutation showed mild clinical symptoms and vacuolar changes in muscle. In our family, the phenotype encompasses additionally a mild demyelinating polyneuropathic syndrome. Thus STM and LGMD2H are the result of loss of function mutations that can be either deletions or missense mutations. (c) 2009 Wiley-Liss, Inc.

  • 4. Fonseca, Luis Vazquez
    et al.
    Doimo, Mara
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics. Clinical Genetics Unit, Department of Women and Children's Health, IRP Città della Speranza, University of Padova, Padova, Italy.
    Calderan, Cristina
    Desbats, Maria Andrea
    Acosta, Manuel J.
    Cerqua, Cristina
    Cassina, Matteo
    Ashraf, Shazia
    Hildebrandt, Friedhelm
    Sartori, Geppo
    Navas, Placido
    Trevisson, Eva
    Salviati, Leonardo
    Mutations in COQ8B (ADCK4) found in patients with steroid-resistant nephrotic syndrome alter COQ8B function2018In: Human Mutation, ISSN 1059-7794, E-ISSN 1098-1004, Vol. 39, no 3, p. 406-414Article in journal (Refereed)
    Abstract [en]

    Mutations in COQ8B cause steroid-resistant nephrotic syndrome with variable neurological involvement. In yeast, COQ8 encodes a protein required for coenzyme Q (CoQ) biosynthesis, whose precise role is not clear. Humans harbor two paralog genes: COQ8A and COQ8B (previously termed ADCK3 and ADCK4). We have found that COQ8B is a mitochondrial matrix protein peripherally associated with the inner membrane. COQ8B can complement a Delta COQ8 yeast strain when its mitochondrial targeting sequence (MTS) is replaced by a yeast MTS. This model was employed to validate COQ8B mutations, and to establish genotype-phenotype correlations. All mutations affected respiratory growth, but there was no correlation between mutation type and the severity of the phenotype. In fact, contrary to the case of COQ2, where residual CoQ biosynthesis correlates with clinical severity, patients harboring hypomorphic COQ8B alleles did not display a different phenotype compared with those with null mutations. These data also suggest that the system is redundant, and that other proteins (probably COQ8A) may partially compensate for the absence of COQ8B. Finally, a COQ8B polymorphism, present in 50% of the European population (NM_024876.3:c.521A > G, p.His174Arg), affects stability of the protein and could represent a risk factor for secondary CoQ deficiencies or for other complex traits.

  • 5.
    Jonsson, Frida
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Byström, Berit
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Ophthalmology.
    Davidson, Alice E.
    UCL Institute of Ophthalmology, London, UK.
    Backman, Ludvig J.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Kellgren, Therese
    Umeå University, Faculty of Science and Technology, Department of Mathematics and Mathematical Statistics.
    Tuft, Stephen J.
    UCL Institute of Ophthalmology, London, UK; Moorfields Eye Hospital, London, UK.
    Koskela, Timo
    Koskelas Eye Clinic, Umeå, Sweden.
    Ryden, Patrik
    Umeå University, Faculty of Science and Technology, Department of Mathematics and Mathematical Statistics.
    Sandgren, Ola
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Ophthalmology.
    Danielson, Patrik
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Hardcastle, Alison J.
    UCL Institute of Ophthalmology, London, UK.
    Golovleva, Irina
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Mutations in Collagen, Type XVII, Alpha 1 (COL17A1) Cause Epithelial Recurrent Erosion Dystrophy (ERED)2015In: Human Mutation, ISSN 1059-7794, E-ISSN 1098-1004, Vol. 36, no 4, p. 463-473Article in journal (Refereed)
    Abstract [en]

    Corneal dystrophies are a clinically and genetically heterogeneous group of inherited disorders that bilaterally affect corneal transparency. They are defined according to the corneal layer affected and by their genetic cause. In this study, we identified a dominantly inherited epithelial recurrent erosion dystrophy (ERED)-like disease that is common in northern Sweden. Whole-exome sequencing resulted in the identification of a novel mutation, c.2816C>T, p.T939I, in the COL17A1 gene, which encodes collagen type XVII alpha 1. The variant segregated with disease in a genealogically expanded pedigree dating back 200 years. We also investigated a unique COL17A1 synonymous variant, c.3156C>T, identified in a previously reported unrelated dominant ERED-like family linked to a locus on chromosome 10q23-q24 encompassing COL17A1. We show that this variant introduces a cryptic donor site resulting in aberrant pre-mRNA splicing and is highly likely to be pathogenic. Bi-allelic COL17A1 mutations have previously been associated with a recessive skin disorder, junctional epidermolysis bullosa, with recurrent corneal erosions being reported in some cases. Our findings implicate presumed gain-of-function COL17A1 mutations causing dominantly inherited ERED and improve understanding of the underlying pathology.

  • 6. Lindqvist, Carl Marten
    et al.
    Nordlund, Jessica
    Ekman, Diana
    Johansson, Anna
    Moghadam, Behrooz Torabi
    Raine, Amanda
    Overnas, Elin
    Dahlberg, Johan
    Wahlberg, Per
    Henriksson, Niklas
    Abrahamsson, Jonas
    Frost, Britt-Marie
    Grander, Dan
    Heyman, Mats
    Larsson, Rolf
    Palle, Josefine
    Soderhall, Stefan
    Forestier, Erik
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Lonnerholm, Gudmar
    Syvanen, Ann-Christine
    Berglund, Eva C.
    The Mutational Landscape in Pediatric Acute Lymphoblastic Leukemia Deciphered by Whole Genome Sequencing2015In: Human Mutation, ISSN 1059-7794, E-ISSN 1098-1004, Vol. 36, no 1, p. 118-128Article in journal (Refereed)
    Abstract [en]

    Genomic characterization of pediatric acute lymphoblastic leukemia (ALL) has identified distinct patterns of genes and pathways altered in patients with well-defined genetic aberrations. To extend the spectrum of known somatic variants in ALL, we performed whole genome and transcriptome sequencing of three B-cell precursor patients, of which one carried the t(12;21)ETV6-RUNX1 translocation and two lacked a known primary genetic aberration, and one T-ALL patient. We found that each patient had a unique genome, with a combination of well-known and previously undetected genomic aberrations. By targeted sequencing in 168 patients, we identified KMT2D and KIF1B as novel putative driver genes. We also identified a putative regulatory non-coding variant that coincided with overexpression of the growth factor MDK. Our results contribute to an increased understanding of the biological mechanisms that lead to ALL and suggest that regulatory variants may be more important for cancer development than recognized to date. The heterogeneity of the genetic aberrations in ALL renders whole genome sequencing particularly well suited for analysis of somatic variants in both research and diagnostic applications.

  • 7. Lombardi, Maria Paola
    et al.
    Bulk, Saskia
    Celli, Jacopo
    Lampe, Anne
    Gabbett, Michael T
    Ousager, Lillian Bomme
    van der Smagt, Jasper J
    Soller, Maria
    Stattin, Eva-Lena
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Mannens, Marcel A M M
    Smigiel, Robert
    Hennekam, Raoul C
    Mutation update for the PORCN gene2011In: Human Mutation, ISSN 1059-7794, E-ISSN 1098-1004, Vol. 32, no 7, p. 723-728Article in journal (Refereed)
    Abstract [en]

    Mutations in the PORCN gene were first identified in Goltz-Gorlin syndrome patients in 2007. Since then, several reports have been published describing a large variety of genetic defects resulting in the Goltz-Gorlin syndrome, and mutations or deletions were also reported in angioma serpiginosum, the pentalogy of Cantrell and Limb-Body Wall Complex. Here we present a review of the published mutations in the PORCN gene to date and report on seven new mutations together with the corresponding clinical data. Based on the review we have created a Web-based locus-specific database that lists all identified variants and allows the inclusion of future reports. The database is based on the Leiden Open (source) Variation Database (LOVD) software, and is accessible online at http://www.lovd.nl/porcn. At present, the database contains 106 variants, representing 68 different mutations, scattered along the whole coding sequence of the PORCN gene, and 12 large gene rearrangements, which brings up to 80 the number of unique mutations identified in Goltz-Gorlin syndrome patients.

  • 8. Mackay, Donna S
    et al.
    Borman, Arundhati Dev
    Sui, Ruifang
    van den Born, L Ingeborgh
    Berson, Eliot L
    Ocaka, Louise A
    Davidson, Alice E
    Heckenlively, John R
    Branham, Kari
    Ren, Huanan
    Lopez, Irma
    Maria, Maleeha
    Azam, Maleeha
    Henkes, Arjen
    Blokland, Ellen
    Andreasson, Sten
    de Baere, Elfride
    Bennett, Jean
    Chader, Gerald J
    Berger, Wolfgang
    Golovleva, Irina
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Greenberg, Jacquie
    den Hollander, Anneke I
    Klaver, Caroline C W
    Klevering, B Jeroen
    Lorenz, Birgit
    Preising, Markus N
    Ramsear, Raj
    Roberts, Lisa
    Roepman, Ronald
    Rohrschneider, Klaus
    Wissinger, Bernd
    Qamar, Raheel
    Webster, Andrew R
    Cremers, Frans P M
    Moore, Anthony T
    Koenekoop, Robert K
    Screening of a Large Cohort of Leber Congenital Amaurosis and Retinitis Pigmentosa Patients Identifies Novel LCA5 Mutations and New Genotype-Phenotype Correlations2013In: Human Mutation, ISSN 1059-7794, E-ISSN 1098-1004, Vol. 34, no 11, p. 1537-1546Article in journal (Refereed)
    Abstract [en]

    This study was undertaken to investigate the prevalence of sequence variants in LCA5 in patients with Leber congenital amaurosis (LCA), early-onset retinal dystrophy (EORD), and autosomal recessive retinitis pigmentosa (arRP); to delineate the ocular phenotypes; and to provide an overview of all published LCA5 variants in an online database. Patients underwent standard ophthalmic evaluations after providing informed consent. In selected patients, optical coherence tomography (OCT) and fundus autofluorescence imaging were possible. DNA samples from 797 unrelated patients with LCA and 211 with the various types of retinitis pigmentosa (RP) were screened by Sanger sequence analysis of all LCA5 exons and intron/exon junctions. Some LCA patients were prescreened by APEX technology or selected based on homozygosity mapping. In silico analyses were performed to assess the pathogenicity of the variants. Segregation analysis was performed where possible. Published and novel LCA5 variants were collected, amended for their correct nomenclature, and listed in a Leiden Open Variation Database (LOVD). Sequence analysis identified 18 new probands with 19 different LCA5 variants. Seventeen of the 19 LCA5 variants were novel. Except for two missense variants and one splice site variant, all variants were protein-truncating mutations. Most patients expressed a severe phenotype, typical of LCA. However, some LCA subjects had better vision and intact inner segment/outer segment (IS/OS) junctions on OCT imaging. In two families with LCA5 variants, the phenotype was more compatible with EORD with affected individuals displaying preserved islands of retinal pigment epithelium. One of the families with a milder phenotype harbored a homozygous splice site mutation; a second family was found to have a combination of a stop mutation and a missense mutation. This is the largest LCA5 study to date. We sequenced 1,008 patients (797 with LCA, 211 with arRP) and identified 18 probands with LCA5 mutations. Mutations in LCA5 are a rare cause of childhood retinal dystrophy accounting for ∼2% of disease in this cohort, and the majority of LCA5 mutations are likely null. The LCA5 protein truncating mutations are predominantly associated with LCA. However, in two families with the milder EORD, the LCA5 gene analysis revealed a homozygous splice site mutation in one and a stop mutation in combination with a missense mutation in a second family, suggesting that this milder phenotype is due to residual function of lebercilin and expanding the currently known phenotypic spectrum to include the milder early onset RP. Some patients have remaining foveal cone structures (intact IS/OS junctions on OCT imaging) and remaining visual acuities, which may bode well for upcoming treatment trials.

  • 9.
    Nordin, Angelica
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Larsson, Elin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Holmberg, Monica
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    The defective splicing caused by the ISCU intron mutation in patients with myopathy with lactic acidosis is repressed by PTBP1 but can be de-repressed by IGF2BP12012In: Human Mutation, ISSN 1059-7794, E-ISSN 1098-1004, Vol. 33, no 3, p. 467-470Article in journal (Refereed)
    Abstract [en]

    Hereditary myopathy with lactic acidosis (HML) is caused by an intron mutation in the iron-sulfur cluster assembly gene ISCU which leads to the activation of cryptic splice sites and the retention of part of intron 4. This incorrect splicing is more pronounced in muscle than in other tissues, resulting in a muscle-specific phenotype. In this study, we identified five nuclear factors that interact with the sequence harboring the mutation and analyzed their effect on the splicing of the ISCU gene. The identification revealed three splicing factors, SFRS14, RBM39 and PTBP1, and two additional RNA binding factors, matrin 3 (MATR3) and IGF2BP1. IGF2BP1 showed a preference for the mutant sequence, whereas the other factors showed similar affinity for both sequences. PTBP1 was found to repress the defective splicing of ISCU, resulting in a drastic loss of mutant transcripts. In contrast, IGF2BP1 and RBM39 shifted the splicing ratio toward the incorrect splice form.

  • 10. Ramus, Susan J
    et al.
    Antoniou, Antonis C
    Kuchenbaecker, Karoline B
    Soucy, Penny
    Beesley, Jonathan
    Chen, Xiaoqing
    McGuffog, Lesley
    Sinilnikova, Olga M
    Healey, Sue
    Barrowdale, Daniel
    Lee, Andrew
    Thomassen, Mads
    Gerdes, Anne-Marie
    Kruse, Torben A
    Birk Jensen, Uffe
    Skytte, Anne-Bine
    Caligo, Maria A
    Liljegren, Annelie
    Lindblom, Annika
    Olsson, Håkan
    Kristoffersson, Ulf
    Stenmark-Askmalm, Marie
    Melin, Beatrice
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Domchek, Susan M
    Nathanson, Katherine L
    Rebbeck, Timothy R
    Jakubowska, Anna
    Lubinski, Jan
    Jaworska, Katarzyna
    Durda, Katarzyna
    Złowocka, Elżbieta
    Gronwald, Jacek
    Huzarski, Tomasz
    Byrski, Tomasz
    Cybulski, Cezary
    Toloczko-Grabarek, Aleksandra
    Osorio, Ana
    Benitez, Javier
    Duran, Mercedes
    Tejada, M Isabel
    Hamann, Ute
    Rookus, Matti
    van Leeuwen, Flora E
    Aalfs, Cora M
    Meijers-Heijboer, Hanne E J
    van Asperen, Christi J
    van Roozendaal, K E P
    Hoogerbrugge, Nicoline
    Margriet Collée, J
    Kriege, Mieke
    van der Luijt, Rob B
    Peock, Susan
    Frost, Debra
    Ellis, Steve D
    Platte, Radka
    Fineberg, Elena
    Evans, D Gareth
    Lalloo, Fiona
    Jacobs, Chris
    Eeles, Ros
    Adlard, Julian
    Davidson, Rosemarie
    Eccles, Diana
    Cole, Trevor
    Cook, Jackie
    Paterson, Joan
    Douglas, Fiona
    Brewer, Carole
    Hodgson, Shirley
    Morrison, Patrick J
    Walker, Lisa
    Porteous, Mary E
    Kennedy, M John
    Pathak, Harsh
    Godwin, Andrew K
    Stoppa-Lyonnet, Dominique
    Caux-Moncoutier, Virginie
    de Pauw, Antoine
    Gauthier-Villars, Marion
    Mazoyer, Sylvie
    Léoné, Mélanie
    Calender, Alain
    Lasset, Christine
    Bonadona, Valérie
    Hardouin, Agnès
    Berthet, Pascaline
    Bignon, Yves-Jean
    Uhrhammer, Nancy
    Faivre, Laurence
    Loustalot, Catherine
    Buys, Saundra
    Daly, Mary
    Miron, Alex
    Beth Terry, Mary
    Chung, Wendy
    John, Esther M
    Southey, Melissa
    Goldgar, David
    Singer, Christian F
    Tea Maria, Muy-Kheng
    Pfeiler, Georg
    Fink-Retter, Anneliese
    Hansen, Thomas V O
    Ejlertsen, Bent
    Johannsson, Oskar Th
    Offit, Kenneth
    Kirchhoff, Tomas
    Gaudet, Mia M
    Vijai, Joseph
    Robson, Mark
    Piedmonte, Marion
    Phillips, Kelly-Anne
    Van Le, Linda
    Hoffman, James S
    Toland, Amanda Ewart
    Montagna, Marco
    Tognazzo, Silvia
    Imyanitov, Evgeny
    Isaacs, Claudine
    Janavicius, Ramunas
    Lazaro, Conxi
    Blanco, Ignacio
    Tornero, Eva
    Navarro, Matilde
    Moysich, Kirsten B
    Karlan, Beth Y
    Gross, Jenny
    Olah, Edith
    Vaszko, Tibor
    Teo, Soo-Hwang
    Ganz, Patricia A
    Beattie, Mary S
    Dorfling, Cecelia M
    van Rensburg, Elizabeth J
    Diez, Orland
    Kwong, Ava
    Schmutzler, Rita K
    Wappenschmidt, Barbara
    Engel, Christoph
    Meindl, Alfons
    Ditsch, Nina
    Arnold, Norbert
    Heidemann, Simone
    Niederacher, Dieter
    Preisler-Adams, Sabine
    Gadzicki, Dorotehea
    Varon-Mateeva, Raymonda
    Deissler, Helmut
    Gehrig, Andrea
    Sutter, Christian
    Kast, Karin
    Fiebig, Britta
    Schäfer, Dieter
    Caldes, Trinidad
    de la Hoya, Miguel
    Nevanlinna, Heli
    Aittomäki, Kristiina
    Plante, Marie
    Spurdle, Amanda B
    Neuhausen, Susan L
    Ding, Yuan Chun
    Wang, Xianshu
    Lindor, Noralane
    Fredericksen, Zachary
    Pankratz, Vernon S
    Peterlongo, Paolo
    Manoukian, Siranoush
    Peissel, Bernard
    Zaffaroni, Daniela
    Bonanni, Bernardo
    Bernard, Loris
    Dolcetti, Riccardo
    Papi, Laura
    Ottini, Laura
    Radice, Paolo
    Greene, Mark H
    Mai, Phuong L
    Andrulis, Irene L
    Glendon, Gord
    Ozcelik, Hilmi
    Pharoah, Paul D P
    Gayther, Simon A
    Simard, Jacques
    Easton, Douglas F
    Couch, Fergus J
    Chenevix-Trench, Georgia
    Ovarian cancer susceptibility alleles and risk of ovarian cancer in BRCA1 and BRCA2 mutation carriers2012In: Human Mutation, ISSN 1059-7794, E-ISSN 1098-1004, Vol. 33, no 4, p. 690-702Article in journal (Refereed)
    Abstract [en]

    Germline mutations in BRCA1 and BRCA2 are associated with increased risks of breast and ovarian cancer. A genome-wide association study (GWAS) identified six alleles associated with risk of ovarian cancer for women in the general population. We evaluated four of these loci as potential modifiers of ovarian cancer risk for BRCA1 and BRCA2 mutation carriers. Four SNPs, rs10088218 (at 8q24), rs2665390 (at 3q25), rs717852 (at 2q31) and rs9303542 (at 17q21), were genotyped in 12,599 BRCA1 and 7,132 BRCA2 carriers, including 2,678 ovarian cancer cases. Associations were evaluated within a retrospective cohort approach. All four loci were associated with ovarian cancer risk in BRCA2 carriers; rs10088218 per-allele hazard ratio (HR) = 0.81 (95%CI: 0.67-0.98) P-trend = 0.033, rs2665390 HR = 1.48 (95%CI: 1.21-1.83) P-trend = 1.8 × 10, rs717852 HR = 1.25 (95%CI: 1.10-1.42) P-trend = 6.6 × 10(-4) , rs9303542 HR = 1.16 (95%CI: 1.02-1.33) P-trend = 0.026. Two loci were associated with ovarian cancer risk in BRCA1 carriers; rs10088218 per-allele HR = 0.89 (95%CI: 0.81-0.99) P-trend = 0.029, rs2665390 HR = 1.25 (95%CI: 1.10-1.42) P-trend = 6.1 × 10(-4) . The HR estimates for the remaining loci were consistent with odds ratio estimates for the general population. The identification of multiple loci modifying ovarian cancer risk may be useful for counselling women with BRCA1 and BRCA2 mutations regarding their risk of ovarian cancer.

  • 11. Sukalo, Maja
    et al.
    Fiedler, Ariane
    Guzman, Celina
    Spranger, Stephanie
    Addor, Marie-Claude
    Mcheik, Jiad N.
    Benavent, Manuel Oltra
    Cobben, Jan M.
    Gillis, Lynette A.
    Shealy, Amy G.
    Deshpande, Charu
    Bozorgmehr, Bita
    Everman, David B.
    Stattin, Eva-Lena
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Liebelt, Jan
    Keller, Klaus-Michael
    Bertola, Debora Romeo
    van Karnebeek, Clara D. M.
    Bergmann, Carsten
    Liu, Zhifeng
    Dueker, Gesche
    Rezaei, Nima
    Alkuraya, Fowzan S.
    Ogur, Gonul
    Alrajoudi, Abdullah
    Venegas-Vega, Carlos A.
    Verbeek, Nienke E.
    Richmond, Erick J.
    Kirbiyik, Ozgur
    Ranganath, Prajnya
    Singh, Ankur
    Godbole, Koumudi
    Ali, Fouad A. M.
    Alves, Cresio
    Mayerle, Julia
    Lerch, Markus M.
    Witt, Heiko
    Zenker, Martin
    Mutations in the Human UBR1 Gene and the Associated Phenotypic Spectrum2014In: Human Mutation, ISSN 1059-7794, E-ISSN 1098-1004, Vol. 35, no 5, p. 521-531Article in journal (Refereed)
    Abstract [en]

    Johanson-Blizzard syndrome (JBS) is a rare, autosomal recessive disorder characterized by exocrine pancreatic insufficiency, typical facial features, dental anomalies, hypothyroidism, sensorineural hearing loss, scalp defects, urogenital and anorectal anomalies, short stature, and cognitive impairment of variable degree. This syndrome is caused by a defect of the E3 ubiquitin ligase UBR1, which is part of the proteolytic N-end rule pathway. Herein, we review previously reported (n=29) and a total of 31 novel UBR1 mutations in relation to the associated phenotype in patients from 50 unrelated families. Mutation types include nonsense, frameshift, splice site, missense, and small in-frame deletions consistent with the hypothesis that loss of UBR1 protein function is the molecular basis of JBS. There is an association of missense mutations and small in-frame deletions with milder physical abnormalities and a normal intellectual capacity, thus suggesting that at least some of these may represent hypomorphic UBR1 alleles. The review of clinical data of a large number of molecularly confirmed JBS cases allows us to define minimal clinical criteria for the diagnosis of JBS. For all previously reported and novel UBR1 mutations together with their clinical data, a mutation database has been established at LOVD.

  • 12. van Doormaal, Perry T. C.
    et al.
    Ticozzi, Nicola
    Weishaupt, Jochen H.
    Kenna, Kevin
    Diekstra, Frank P.
    Verde, Federico
    Andersen, Peter M.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Dekker, Annelot M.
    Tiloca, Cinzia
    Marroquin, Nicolai
    Overste, Daniel J.
    Pensato, Viviana
    Nuernberg, Peter
    Pulit, Sara L.
    Schellevis, Raymond D.
    Calini, Daniela
    Altmueller, Janine
    Francioli, Laurent C.
    Muller, Bernard
    Castellotti, Barbara
    Motameny, Susanne
    Ratti, Antonia
    Wolf, Joachim
    Gellera, Cinzia
    Ludolph, Albert C.
    van den Berg, Leonard H.
    Kubisch, Christian
    Landers, John E.
    Veldink, Jan H.
    Silani, Vincenzo
    Volk, Alexander E.
    The role of de novo mutations in the development of amyotrophic lateral sclerosis2017In: Human Mutation, ISSN 1059-7794, E-ISSN 1098-1004, Vol. 38, no 11, p. 1534-1541Article in journal (Refereed)
    Abstract [en]

    The genetic basis combined with the sporadic occurrence of amyotrophic lateral sclerosis (ALS) suggests a role of de novo mutations in disease pathogenesis. Previous studies provided some evidence for this hypothesis; however, results were conflicting: no genes with recurrent occurring de novo mutations were identified and different pathways were postulated. In this study, we analyzed whole-exome data from 82 new patient-parents trios and combined it with the datasets of all previously published ALS trios (173 trios in total). The per patient de novo rate was not higher than expected based on the general population (P = 0.40). We showed that these mutations are not part of the previously postulated pathways, and gene-gene interaction analysis found no enrichment of interacting genes in this group (P = 0.57). Also, we were able to show that the de novo mutations in ALS patients are located in genes already prone for de novo mutations (P < 1 x 10(-15)). Although the individual effect of rare de novo mutations in specific genes could not be assessed, our results indicate that, in contrast to previous hypothesis, de novo mutations in general do not impose a major burden on ALS risk.

  • 13. Wang, Zhaoming
    et al.
    Rajaraman, Preetha
    Melin, Beatrice S.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Chung, Charles C.
    Zhang, Weijia
    McKean-Cowdin, Roberta
    Michaud, Dominique
    Yeager, Meredith
    Ahlbom, Anders
    Albanes, Demetrius
    Andersson, Ulrika
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Freeman, Laura E. Beane
    Buring, Julie E.
    Butler, Mary Ann
    Carreon, Tania
    Feychting, Maria
    Gapstur, Susan M.
    Gaziano, J. Michael
    Giles, Graham G.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Biobank Research. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Henriksson, Roger
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Hoffman-Bolton, Judith
    Inskip, Peter D.
    Kitahara, Cari M.
    Marchand, Loic Le
    Linet, Martha S.
    Li, Shengchao
    Peters, Ulrike
    Purdue, Mark P.
    Rothman, Nathaniel
    Ruder, Avima M.
    Sesso, Howard D.
    Severi, Gianluca
    Stampfer, Meir
    Stevens, Victoria L.
    Visvanathan, Kala
    Wang, Sophia S.
    White, Emily
    Zeleniuch-Jacquotte, Anne
    Hoover, Robert
    Fraumeni, Joseph F.
    Chatterjee, Nilanjan
    Hartge, Patricia
    Chanock, Stephen J.
    Further Confirmation of Germline Glioma Risk Variant rs78378222 in TP53 and Its Implication in Tumor Tissues via Integrative Analysis of TCGA Data2015In: Human Mutation, ISSN 1059-7794, E-ISSN 1098-1004, Vol. 36, no 7, p. 684-688Article in journal (Refereed)
    Abstract [en]

    We confirmed strong association of rs78378222:A>C (per allele odds ratio [OR] = 3.14; P = 6.48 x 10(-11)), a germline rare single-nucleotide polymorphism (SNP) in TP53, via imputation of a genome-wide association study of glioma (1,856 cases and 4,955 controls). We subsequently performed integrative analyses on the Cancer Genome Atlas (TCGA) data for GBM (glioblastoma multiforme) and LUAD (lung adenocarcinoma). Based on SNP data, we imputed genotypes for rs78378222 and selected individuals carrying rare risk allele (C). Using RNA sequencing data, we observed aberrant transcripts with approximate to 3 kb longer than normal for those individuals. Using exome sequencing data, we further showed that loss of haplotype carrying common protective allele (A) occurred somatically in GBM but not in LUAD. Our bioinformatic analysis suggests rare risk allele (C) disrupts mRNA termination, and an allelic loss of a genomic region harboring common protective allele (A) occurs during tumor initiation or progression for glioma.

  • 14. Weisschuh, Nicole
    et al.
    Stingl, Katarina
    Audo, Isabelle
    Biskup, Saskia
    Bocquet, Beatrice
    Branham, Kari
    Burstedt, Marie
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Ophthalmology.
    De Baere, Elfride
    De Vries, Meindert J.
    Golovleva, Irina
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Green, Andrew
    Heckenlively, John
    Leroy, Bart P.
    Meunier, Isabelle
    Traboulsi, Elias
    Wissinger, Bernd
    Kohl, Susanne
    Mutations in the gene PDE6C encoding the catalytic subunit of the cone photoreceptor phosphodiesterase in patients with achromatopsia2018In: Human Mutation, ISSN 1059-7794, E-ISSN 1098-1004, Vol. 39, no 10, p. 1366-1371Article in journal (Refereed)
    Abstract [en]

    Biallelic PDE6C mutations are a known cause for rod monochromacy, better known as autosomal recessive achromatopsia (ACHM), and early-onset cone photoreceptor dysfunction. PDE6C encodes the catalytic alpha'-subunit of the cone photoreceptor phosphodiesterase, thereby constituting an essential part of the phototransduction cascade. Here, we present the results of a study comprising 176 genetically preselected patients who remained unsolved after Sanger sequencing of the most frequent genes accounting for ACHM, and were subsequently screened for exonic and splice site variants in PDE6C applying a targeted next generation sequencing approach. We were able to identify potentially pathogenic biallelic variants in 15 index cases. The mutation spectrum comprises 18 different alleles, 15 of which are novel. Our study significantly contributes to the mutation spectrum of PDE6C and allows for a realistic estimate of the prevalence of PDE6C mutations in ACHM since our entire ACHM cohort comprises 1,074 independent families.

  • 15. Wennberg, Charlotte
    et al.
    Kozlenkov, Alexey
    Umeå University, Faculty of Medicine, Medical Biosciences.
    Mauro, Sonia Di
    Fröhlander, Nils
    Beckman, Lars
    Hoylaerts, Marc F.
    Millán, José Luis
    Structure, genomic DNA typing and kinetic characterization of the D allozyme of placental alkaline phosphatase2002In: Human Mutation, ISSN 1059-7794, E-ISSN 1098-1004, Vol. 19, no 3, p. 258-267Article in journal (Refereed)
    Abstract [en]

    The D allozyme of placental alkaline phosphatase (PLAP) displays enzymatic properties at variance with those of the common PLAP allozymes. We have deduced the amino acid sequence of the PLAP D allele by PCR cloning of its gene, ALPP. Two coding substitutions were found in comparison with the cDNA of the common PLAP F allele, i.e., 692C>G and 1352A>G, which translate into a P209R and E429G substitution. A single nucleotide primer extension (SNuPE) assay was developed using PCR primers that enable the amplification of a 1.9 kb PLAP fragment. Extension primers were then used on this PCR fragment to detect the 692C>G and 1352A>G substitution. The SNuPE assay on these two nucleotide substitutions enabled us to distinguish the PLAP F and D alleles from the PLAP S/I alleles. Functional studies on the D allozyme were made possible by constructing and expressing a PLAP D cDNA, i.e., [Arg209, Gly429]PLAP, into wild-type Chinese hamster ovary cells. We determined the kcat and Km, of the PLAP S, F, and D allozymes using the non-physiological substrate p-nitrophenylphosphate at an optimal pH (9.8) as well as two physiological substrates, i.e., pyridoxal-5-phosphate and inorganic pyrophosphate at physiological pH (7.5). We found that the biochemical properties of the D allozyme of PLAP are significantly different from those of the common PLAP allozymes. These biochemical findings suggest that a suboptimal enzymatic function by the PLAP D allozyme may be the basis for the apparent negative selective pressure of the PLAP D allele. The development of the SNuPE assay will enable us to test the hypothesis that the PLAP D allele is subjected to intrauterine selection by examining genomic DNA from statistically informative population samples.

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