• Je něco špatně v tomto záznamu ?

Bi-allelic ADARB1 Variants Associated with Microcephaly, Intellectual Disability, and Seizures

TY. Tan, J. Sedmík, MP. Fitzgerald, RS. Halevy, LP. Keegan, I. Helbig, L. Basel-Salmon, L. Cohen, R. Straussberg, WK. Chung, M. Helal, R. Maroofian, H. Houlden, J. Juusola, S. Sadedin, L. Pais, KB. Howell, SM. White, J. Christodoulou, MA. O'Connell,

. 2020 ; 106 (4) : 467-483. [pub] 20200326

Jazyk angličtina Země Spojené státy americké

Typ dokumentu časopisecké články, Research Support, N.I.H., Extramural, práce podpořená grantem

Perzistentní odkaz   https://www.medvik.cz/link/bmc20023074

Grantová podpora
UM1 HG008900 NHGRI NIH HHS - United States

E-zdroje Online Plný text

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
Elsevier Open Access Journals od 1997-06-01
Elsevier Open Archive Journals od 1997 do Před 6 měsíci

Odkazy

PubMed 32220291
DOI 10.1016/j.ajhg.2020.02.015
Knihovny.cz E-zdroje

The RNA editing enzyme ADAR2 is essential for the recoding of brain transcripts. Impaired ADAR2 editing leads to early-onset epilepsy and premature death in a mouse model. Here, we report bi-allelic variants in ADARB1, the gene encoding ADAR2, in four unrelated individuals with microcephaly, intellectual disability, and epilepsy. In one individual, a homozygous variant in one of the double-stranded RNA-binding domains (dsRBDs) was identified. In the others, variants were situated in or around the deaminase domain. To evaluate the effects of these variants on ADAR2 enzymatic activity, we performed in vitro assays with recombinant proteins in HEK293T cells and ex vivo assays with fibroblasts derived from one of the individuals. We demonstrate that these ADAR2 variants lead to reduced editing activity on a known ADAR2 substrate. We also demonstrate that one variant leads to changes in splicing of ADARB1 transcript isoforms. These findings reinforce the importance of RNA editing in brain development and introduce ADARB1 as a genetic etiology in individuals with intellectual disability, microcephaly, and epilepsy.

Citace poskytuje Crossref.org

000      
00000naa a2200000 a 4500
001      
bmc20023074
003      
CZ-PrNML
005      
20201214125230.0
007      
ta
008      
201125s2020 xxu f 000 0|eng||
009      
AR
024    7_
$a 10.1016/j.ajhg.2020.02.015 $2 doi
035    __
$a (PubMed)32220291
040    __
$a ABA008 $b cze $d ABA008 $e AACR2
041    0_
$a eng
044    __
$a xxu
100    1_
$a Tan, Tiong Yang $u Victorian Clinical Genetics Services, Melbourne 3052, Australia; Murdoch Children's Research Institute, Melbourne 3052, Australia; Department of Pediatrics, University of Melbourne, Melbourne 3052, Australia. Electronic address: tiong.tan@vcgs.org.au.
245    10
$a Bi-allelic ADARB1 Variants Associated with Microcephaly, Intellectual Disability, and Seizures / $c TY. Tan, J. Sedmík, MP. Fitzgerald, RS. Halevy, LP. Keegan, I. Helbig, L. Basel-Salmon, L. Cohen, R. Straussberg, WK. Chung, M. Helal, R. Maroofian, H. Houlden, J. Juusola, S. Sadedin, L. Pais, KB. Howell, SM. White, J. Christodoulou, MA. O'Connell,
520    9_
$a The RNA editing enzyme ADAR2 is essential for the recoding of brain transcripts. Impaired ADAR2 editing leads to early-onset epilepsy and premature death in a mouse model. Here, we report bi-allelic variants in ADARB1, the gene encoding ADAR2, in four unrelated individuals with microcephaly, intellectual disability, and epilepsy. In one individual, a homozygous variant in one of the double-stranded RNA-binding domains (dsRBDs) was identified. In the others, variants were situated in or around the deaminase domain. To evaluate the effects of these variants on ADAR2 enzymatic activity, we performed in vitro assays with recombinant proteins in HEK293T cells and ex vivo assays with fibroblasts derived from one of the individuals. We demonstrate that these ADAR2 variants lead to reduced editing activity on a known ADAR2 substrate. We also demonstrate that one variant leads to changes in splicing of ADARB1 transcript isoforms. These findings reinforce the importance of RNA editing in brain development and introduce ADARB1 as a genetic etiology in individuals with intellectual disability, microcephaly, and epilepsy.
650    _2
$a adenosindeaminasa $x genetika $7 D000243
650    _2
$a alely $7 D000483
650    _2
$a alternativní sestřih $x genetika $7 D017398
650    _2
$a dítě $7 D002648
650    _2
$a předškolní dítě $7 D002675
650    _2
$a genetická predispozice k nemoci $x genetika $7 D020022
650    _2
$a genetická variace $x genetika $7 D014644
650    _2
$a HEK293 buňky $7 D057809
650    _2
$a lidé $7 D006801
650    _2
$a mentální retardace $x genetika $7 D008607
650    _2
$a mužské pohlaví $7 D008297
650    _2
$a mikrocefalie $x genetika $7 D008831
650    _2
$a sestřih RNA $x genetika $7 D012326
650    _2
$a proteiny vázající RNA $x genetika $7 D016601
650    _2
$a záchvaty $x genetika $7 D012640
655    _2
$a časopisecké články $7 D016428
655    _2
$a Research Support, N.I.H., Extramural $7 D052061
655    _2
$a práce podpořená grantem $7 D013485
700    1_
$a Sedmík, Jiří $u Central European Institute of Technology, Masaryk University, Kamenice 735/5, A35, Brno 62500, Czech Republic.
700    1_
$a Fitzgerald, Mark P $u Division of Neurology, Departments of Neurology and Pediatrics, The Children's Hospital of Philadelphia and the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; The Epilepsy NeuroGenetics Initiative, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
700    1_
$a Halevy, Rivka Sukenik $u Raphael Recanati Genetic Institute, Rabin Medical Center-Beilinson Hospital, Petah Tikva 49100, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel.
700    1_
$a Keegan, Liam P $u Central European Institute of Technology, Masaryk University, Kamenice 735/5, A35, Brno 62500, Czech Republic.
700    1_
$a Helbig, Ingo $u Division of Neurology, Departments of Neurology and Pediatrics, The Children's Hospital of Philadelphia and the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; The Epilepsy NeuroGenetics Initiative, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
700    1_
$a Basel-Salmon, Lina $u Raphael Recanati Genetic Institute, Rabin Medical Center-Beilinson Hospital, Petah Tikva 49100, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel; Felsenstein Medical Research Center, Petah Tikva 49100, Israel.
700    1_
$a Cohen, Lior $u Pediatric Genetics Unit, Schneider Children's Medical Center of Israel, Petah Tikva 49100, Israel.
700    1_
$a Straussberg, Rachel $u Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel; Pediatric Neurology Unit, Schneider Children's Medical Center of Israel, Petah Tikva 49100, Israel.
700    1_
$a Chung, Wendy K $u Department of Pediatrics, Columbia University Medical Center, New York, NY 10032, USA.
700    1_
$a Helal, Mayada $u Department of Pediatrics, Columbia University Medical Center, New York, NY 10032, USA.
700    1_
$a Maroofian, Reza $u Department of Neuromuscular Disorders, University College London Queen Square Institute of Neurology, London WC1N 3BG, UK.
700    1_
$a Houlden, Henry $u Department of Neuromuscular Disorders, University College London Queen Square Institute of Neurology, London WC1N 3BG, UK.
700    1_
$a Juusola, Jane $u GeneDx, Gaithersburg, MD 20877, USA.
700    1_
$a Sadedin, Simon $u Victorian Clinical Genetics Services, Melbourne 3052, Australia; Murdoch Children's Research Institute, Melbourne 3052, Australia.
700    1_
$a Pais, Lynn $u Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
700    1_
$a Howell, Katherine B $u Murdoch Children's Research Institute, Melbourne 3052, Australia; Department of Pediatrics, University of Melbourne, Melbourne 3052, Australia; Department of Neurology, Royal Children's Hospital, Parkville 3052, Australia.
700    1_
$a White, Susan M $u Victorian Clinical Genetics Services, Melbourne 3052, Australia; Murdoch Children's Research Institute, Melbourne 3052, Australia; Department of Pediatrics, University of Melbourne, Melbourne 3052, Australia.
700    1_
$a Christodoulou, John $u Victorian Clinical Genetics Services, Melbourne 3052, Australia; Murdoch Children's Research Institute, Melbourne 3052, Australia; Department of Pediatrics, University of Melbourne, Melbourne 3052, Australia.
700    1_
$a O'Connell, Mary A $u Central European Institute of Technology, Masaryk University, Kamenice 735/5, A35, Brno 62500, Czech Republic. Electronic address: mary.oconnell@ceitec.muni.cz.
773    0_
$w MED00000254 $t American journal of human genetics $x 1537-6605 $g Roč. 106, č. 4 (2020), s. 467-483
856    41
$u https://pubmed.ncbi.nlm.nih.gov/32220291 $y Pubmed
910    __
$a ABA008 $b sig $c sign $y a $z 0
990    __
$a 20201125 $b ABA008
991    __
$a 20201214125230 $b ABA008
999    __
$a ok $b bmc $g 1595393 $s 1113750
BAS    __
$a 3
BAS    __
$a PreBMC
BMC    __
$a 2020 $b 106 $c 4 $d 467-483 $e 20200326 $i 1537-6605 $m American journal of human genetics $n Am J Hum Genet $x MED00000254
GRA    __
$a UM1 HG008900 $p NHGRI NIH HHS $2 United States
LZP    __
$a Pubmed-20201125

Najít záznam

Citační ukazatele

Možnosti archivace