-
Je něco špatně v tomto záznamu ?
De Novo Heterozygous POLR2A Variants Cause a Neurodevelopmental Syndrome with Profound Infantile-Onset Hypotonia
HA. Haijes, MJE. Koster, H. Rehmann, D. Li, H. Hakonarson, G. Cappuccio, M. Hancarova, D. Lehalle, W. Reardon, GB. Schaefer, A. Lehman, IMBH. van de Laar, CD. Tesselaar, C. Turner, A. Goldenberg, S. Patrier, J. Thevenon, M. Pinelli, N....
Jazyk angličtina Země Spojené státy americké
Typ dokumentu časopisecké články, práce podpořená grantem
Grantová podpora
NV17-29423A
MZ0
CEP - Centrální evidence projektů
Digitální knihovna NLK
Plný text - Článek
NLK
Cell Press Free Archives
od 1997-01-01 do Před 6 měsíci
Free Medical Journals
od 1949 do Před 6 měsíci
PubMed Central
od 1949 do Před 6 měsíci
Europe PubMed Central
od 1949 do Před 6 měsíci
Open Access Digital Library
od 2005-01-01
- MeSH
- dítě MeSH
- DNA řízené RNA-polymerasy genetika MeSH
- fenotyp MeSH
- HeLa buňky MeSH
- heterozygot MeSH
- lidé MeSH
- mladiství MeSH
- mutace * MeSH
- neurovývojové poruchy enzymologie genetika patologie MeSH
- předškolní dítě MeSH
- Saccharomyces cerevisiae genetika růst a vývoj metabolismus MeSH
- svalová hypotonie enzymologie genetika patologie MeSH
- věk při počátku nemoci MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- mladiství MeSH
- mužské pohlaví MeSH
- předškolní dítě MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
The RNA polymerase II complex (pol II) is responsible for transcription of all ∼21,000 human protein-encoding genes. Here, we describe sixteen individuals harboring de novo heterozygous variants in POLR2A, encoding RPB1, the largest subunit of pol II. An iterative approach combining structural evaluation and mass spectrometry analyses, the use of S. cerevisiae as a model system, and the assessment of cell viability in HeLa cells allowed us to classify eleven variants as probably disease-causing and four variants as possibly disease-causing. The significance of one variant remains unresolved. By quantification of phenotypic severity, we could distinguish mild and severe phenotypic consequences of the disease-causing variants. Missense variants expected to exert only mild structural effects led to a malfunctioning pol II enzyme, thereby inducing a dominant-negative effect on gene transcription. Intriguingly, individuals carrying these variants presented with a severe phenotype dominated by profound infantile-onset hypotonia and developmental delay. Conversely, individuals carrying variants expected to result in complete loss of function, thus reduced levels of functional pol II from the normal allele, exhibited the mildest phenotypes. We conclude that subtle variants that are central in functionally important domains of POLR2A cause a neurodevelopmental syndrome characterized by profound infantile-onset hypotonia and developmental delay through a dominant-negative effect on pol-II-mediated transcription of DNA.
Center for Applied Genomics the Children's Hospital of Philadelphia Philadelphia PA 19104 USA
Department of Clinical Genetics Odense University Hospital 5000 Odense Denmark
Department of Genetics Centre Hospitalier Universitaire de Dijon 21000 Dijon France
Department of Medicine the University of Melbourne VIC 3010 Melbourne Australia
Department of Pediatrics Amphia Hospital Breda 4818 CK Breda the Netherlands
Department of Pediatrics Duke University School of Medicine Durham North Carolina NC 27710 USA
Department of Translational Medicine Federico 2 University 80126 Naples Italy
Division of Human Genetics the Children's Hospital of Philadelphia Philadelphia PA 19104 USA
German Cancer Consortium 79106 Heidelberg Germany
H C Andersen Children Hospital Odense University Hospital 5000 Odense Denmark
Perelman School of Medicine University of Pennsylvania Philadelphia PA 19104 USA
Telethon Institute of Genetics and Medicine Pozzuoli 80126 Naples Italy
Citace poskytuje Crossref.org
- 000
- 00000naa a2200000 a 4500
- 001
- bmc20006106
- 003
- CZ-PrNML
- 005
- 20200525152053.0
- 007
- ta
- 008
- 200511s2019 xxu f 000 0|eng||
- 009
- AR
- 024 7_
- $a 10.1016/j.ajhg.2019.06.016 $2 doi
- 035 __
- $a (PubMed)31353023
- 040 __
- $a ABA008 $b cze $d ABA008 $e AACR2
- 041 0_
- $a eng
- 044 __
- $a xxu
- 100 1_
- $a Haijes, Hanneke A $u Department of Pediatrics, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht University, 3584 EA Utrecht, the Netherlands; Department of Biomedical Genetics, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht University, 3584 EA Utrecht, the Netherlands; German Cancer Consortium (DKTK) standort Freiburg and German Cancer Research Center (DKFZ), 79106 Heidelberg, Germany.
- 245 10
- $a De Novo Heterozygous POLR2A Variants Cause a Neurodevelopmental Syndrome with Profound Infantile-Onset Hypotonia / $c HA. Haijes, MJE. Koster, H. Rehmann, D. Li, H. Hakonarson, G. Cappuccio, M. Hancarova, D. Lehalle, W. Reardon, GB. Schaefer, A. Lehman, IMBH. van de Laar, CD. Tesselaar, C. Turner, A. Goldenberg, S. Patrier, J. Thevenon, M. Pinelli, N. Brunetti-Pierri, D. Prchalová, M. Havlovicová, M. Vlckova, Z. Sedláček, E. Lopez, V. Ragoussis, AT. Pagnamenta, U. Kini, HR. Vos, RM. van Es, RFMA. van Schaik, TAJ. van Essen, M. Kibaek, JC. Taylor, J. Sullivan, V. Shashi, S. Petrovski, C. Fagerberg, DM. Martin, KLI. van Gassen, R. Pfundt, MJ. Falk, EM. McCormick, HTM. Timmers, PM. van Hasselt,
- 520 9_
- $a The RNA polymerase II complex (pol II) is responsible for transcription of all ∼21,000 human protein-encoding genes. Here, we describe sixteen individuals harboring de novo heterozygous variants in POLR2A, encoding RPB1, the largest subunit of pol II. An iterative approach combining structural evaluation and mass spectrometry analyses, the use of S. cerevisiae as a model system, and the assessment of cell viability in HeLa cells allowed us to classify eleven variants as probably disease-causing and four variants as possibly disease-causing. The significance of one variant remains unresolved. By quantification of phenotypic severity, we could distinguish mild and severe phenotypic consequences of the disease-causing variants. Missense variants expected to exert only mild structural effects led to a malfunctioning pol II enzyme, thereby inducing a dominant-negative effect on gene transcription. Intriguingly, individuals carrying these variants presented with a severe phenotype dominated by profound infantile-onset hypotonia and developmental delay. Conversely, individuals carrying variants expected to result in complete loss of function, thus reduced levels of functional pol II from the normal allele, exhibited the mildest phenotypes. We conclude that subtle variants that are central in functionally important domains of POLR2A cause a neurodevelopmental syndrome characterized by profound infantile-onset hypotonia and developmental delay through a dominant-negative effect on pol-II-mediated transcription of DNA.
- 650 _2
- $a mladiství $7 D000293
- 650 _2
- $a věk při počátku nemoci $7 D017668
- 650 _2
- $a dítě $7 D002648
- 650 _2
- $a předškolní dítě $7 D002675
- 650 _2
- $a DNA řízené RNA-polymerasy $x genetika $7 D012321
- 650 _2
- $a ženské pohlaví $7 D005260
- 650 _2
- $a HeLa buňky $7 D006367
- 650 _2
- $a heterozygot $7 D006579
- 650 _2
- $a lidé $7 D006801
- 650 _2
- $a mužské pohlaví $7 D008297
- 650 _2
- $a svalová hypotonie $x enzymologie $x genetika $x patologie $7 D009123
- 650 12
- $a mutace $7 D009154
- 650 _2
- $a neurovývojové poruchy $x enzymologie $x genetika $x patologie $7 D065886
- 650 _2
- $a fenotyp $7 D010641
- 650 _2
- $a Saccharomyces cerevisiae $x genetika $x růst a vývoj $x metabolismus $7 D012441
- 655 _2
- $a časopisecké články $7 D016428
- 655 _2
- $a práce podpořená grantem $7 D013485
- 700 1_
- $a Koster, Maria J E $u Regenerative Medicine Center and Center for Molecular Medicine, University Medical Center Utrecht, Utrecht University, 3584 CT Utrecht, the Netherlands; German Cancer Consortium (DKTK) standort Freiburg and German Cancer Research Center (DKFZ), 79106 Heidelberg, Germany.
- 700 1_
- $a Rehmann, Holger $u Expertise Center for Structural Biology, University Medical Center Utrecht, Utrecht University, 3584 CT Utrecht, the Netherlands; Molecular Cancer Research, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht University, Oncode Institute, 3584 CT Utrecht, the Netherlands.
- 700 1_
- $a Li, Dong $u Center for Applied Genomics, the Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
- 700 1_
- $a Hakonarson, Hakon $u Center for Applied Genomics, the Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Division of Human Genetics, the Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
- 700 1_
- $a Cappuccio, Gerarda $u Department of Translational Medicine, Federico II University, 80126 Naples, Italy; Telethon Institute of Genetics and Medicine, Pozzuoli, 80126 Naples, Italy.
- 700 1_
- $a Hancarova, Miroslava $u Department of Biology and Medical Genetics, Charles University Second Faculty of Medicine and University Hospital Motol, 150 06 Prague, Czech Republic.
- 700 1_
- $a Lehalle, Daphne $u Department of Genetics, Centre Hospitalier Universitaire de Dijon, 21000 Dijon, France.
- 700 1_
- $a Reardon, Willie $u Department of Clinical and Medical Genetics, Our Lady's Hospital for Sick Children, D12 N512 Dublin, Ireland.
- 700 1_
- $a Schaefer, G Bradley $u Department of Pediatrics, Section of Genetics and Metabolism, University of Arkansas for Medical Sciences, Little Rock, Arkansas, AR 72223, USA.
- 700 1_
- $a Lehman, Anna $u Department of Medical Genetics, BC Children's Hospital Research Institute, University of British Columbia, BC V6H 3N1 Vancouver, Canada.
- 700 1_
- $a van de Laar, Ingrid M B H $u Department of Clinical Genetics, Erasmus Medical University Center Rotterdam, 3000 CA Rotterdam, the Netherlands.
- 700 1_
- $a Tesselaar, Coranne D $u Department of Pediatrics, Amphia Hospital Breda, 4818 CK Breda, the Netherlands.
- 700 1_
- $a Turner, Clesson $u Department of Clinical Genetics and Pediatrics, Walter Reed National Military Medical Center, Bethesda, Maryland, MD 20814, USA.
- 700 1_
- $a Goldenberg, Alice $u Department of Genetics, Rouen University Hospital, Centre de Référence Anomalies du Développement, Normandy Centre for Genomic and Personalized Medicine, 76000 Rouen, France.
- 700 1_
- $a Patrier, Sophie $u Department of Pathology, Rouen University Hospital, Centre de Référence Anomalies du Développement, 76000 Rouen, France.
- 700 1_
- $a Thevenon, Julien $u Department of Genetics and Reproduction, Centre Hospitalier Universitaire de Grenoble, 38700 Grenoble, France.
- 700 1_
- $a Pinelli, Michele $u Department of Translational Medicine, Federico II University, 80126 Naples, Italy; Telethon Institute of Genetics and Medicine, Pozzuoli, 80126 Naples, Italy.
- 700 1_
- $a Brunetti-Pierri, Nicola $u Department of Translational Medicine, Federico II University, 80126 Naples, Italy; Telethon Institute of Genetics and Medicine, Pozzuoli, 80126 Naples, Italy.
- 700 1_
- $a Prchalová, Darina $u Department of Biology and Medical Genetics, Charles University Second Faculty of Medicine and University Hospital Motol, 150 06 Prague, Czech Republic.
- 700 1_
- $a Havlovicová, Markéta $u Department of Biology and Medical Genetics, Charles University Second Faculty of Medicine and University Hospital Motol, 150 06 Prague, Czech Republic.
- 700 1_
- $a Vlckova, Markéta $u Department of Biology and Medical Genetics, Charles University Second Faculty of Medicine and University Hospital Motol, 150 06 Prague, Czech Republic.
- 700 1_
- $a Sedláček, Zdeněk $u Department of Biology and Medical Genetics, Charles University Second Faculty of Medicine and University Hospital Motol, 150 06 Prague, Czech Republic.
- 700 1_
- $a Lopez, Elena $u Department of Medical Genetics, BC Children's Hospital Research Institute, University of British Columbia, BC V6H 3N1 Vancouver, Canada.
- 700 1_
- $a Ragoussis, Vassilis $u National Institute for Health Research Oxford Biomedical Research Centre, Wellcome Centre for Human Genetics, University of Oxford, OX3 7BN Oxford, UK.
- 700 1_
- $a Pagnamenta, Alistair T $u National Institute for Health Research Oxford Biomedical Research Centre, Wellcome Centre for Human Genetics, University of Oxford, OX3 7BN Oxford, UK.
- 700 1_
- $a Kini, Usha $u Department of Genomic Medicine, Oxford Centre for Genomic Medicine, Oxford University Hospitals National Health Service Foundation Trust, OX3 7LE Oxford, UK.
- 700 1_
- $a Vos, Harmjan R $u Molecular Cancer Research, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht University, Oncode Institute, 3584 CT Utrecht, the Netherlands.
- 700 1_
- $a van Es, Robert M $u Molecular Cancer Research, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht University, Oncode Institute, 3584 CT Utrecht, the Netherlands.
- 700 1_
- $a van Schaik, Richard F M A $u Molecular Cancer Research, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht University, Oncode Institute, 3584 CT Utrecht, the Netherlands.
- 700 1_
- $a van Essen, Ton A J $u Department of Clinical Genetics, University Medical Center Groningen, 9713 GZ Groningen, the Netherlands.
- 700 1_
- $a Kibaek, Maria $u H.C. Andersen Children Hospital, Odense University Hospital, 5000 Odense, Denmark.
- 700 1_
- $a Taylor, Jenny C $u National Institute for Health Research Oxford Biomedical Research Centre, Wellcome Centre for Human Genetics, University of Oxford, OX3 7BN Oxford, UK.
- 700 1_
- $a Sullivan, Jennifer $u Department of Pediatrics, Duke University School of Medicine, Durham, North Carolina, NC 27710, USA.
- 700 1_
- $a Shashi, Vandana $u Department of Pediatrics, Duke University School of Medicine, Durham, North Carolina, NC 27710, USA.
- 700 1_
- $a Petrovski, Slave $u Department of Pediatrics, Duke University School of Medicine, Durham, North Carolina, NC 27710, USA; AstraZeneca Centre for Genomics Research, Precision Medicine and Genomics, IMED Biotech Unit, AstraZeneca, CB4 0WG Cambridge, United Kingdom; Department of Medicine, the University of Melbourne, VIC 3010 Melbourne, Australia.
- 700 1_
- $a Fagerberg, Christina $u Department of Clinical Genetics, Odense University Hospital, 5000 Odense, Denmark.
- 700 1_
- $a Martin, Donna M $u Departments of Pediatrics and Human Genetics, University of Michigan Medical School, Ann Arbor, Michigan, MI 48109, USA.
- 700 1_
- $a van Gassen, Koen L I $u Department of Biomedical Genetics, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht University, 3584 EA Utrecht, the Netherlands.
- 700 1_
- $a Pfundt, Rolph $u Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center Nijmegen, 6525 HR Nijmegen, the Netherlands.
- 700 1_
- $a Falk, Marni J $u Division of Human Genetics, the Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Mitochondrial Medicine Frontier Program, Division of Human Genetics, the Children's Hospital of Philadelphia, PA 19104, Philadelphia, USA.
- 700 1_
- $a McCormick, Elizabeth M $u Mitochondrial Medicine Frontier Program, Division of Human Genetics, the Children's Hospital of Philadelphia, PA 19104, Philadelphia, USA.
- 700 1_
- $a Timmers, H T Marc $u Regenerative Medicine Center and Center for Molecular Medicine, University Medical Center Utrecht, Utrecht University, 3584 CT Utrecht, the Netherlands; Department of Urology, University Medical Center Freiburg, University of Freiburg, 79110 Freiburg, Germany.
- 700 1_
- $a van Hasselt, Peter M $u Department of Pediatrics, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht University, 3584 EA Utrecht, the Netherlands. Electronic address: p.vanhasselt@umcutrecht.nl.
- 773 0_
- $w MED00000254 $t American journal of human genetics $x 1537-6605 $g Roč. 105, č. 2 (2019), s. 283-301
- 856 41
- $u https://pubmed.ncbi.nlm.nih.gov/31353023 $y Pubmed
- 910 __
- $a ABA008 $b sig $c sign $y a $z 0
- 990 __
- $a 20200511 $b ABA008
- 991 __
- $a 20200525152052 $b ABA008
- 999 __
- $a ok $b bmc $g 1524964 $s 1096162
- BAS __
- $a 3
- BAS __
- $a PreBMC
- BMC __
- $a 2019 $b 105 $c 2 $d 283-301 $e 20190725 $i 1537-6605 $m American journal of human genetics $n Am J Hum Genet $x MED00000254
- GRA __
- $a NV17-29423A $p MZ0
- LZP __
- $a Pubmed-20200511
