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

J 2020

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

TAN, Tiong Yang, Jiří SEDMÍK, Mark P. FITZGERALD, Rivka SUKENIK HALEVY, Liam KEEGAN et. al.

Basic information

Original name

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

Authors

TAN, Tiong Yang, Jiří SEDMÍK (203 Czech Republic, belonging to the institution), Mark P. FITZGERALD, Rivka SUKENIK HALEVY, Liam KEEGAN (372 Ireland, belonging to the institution), Ingo HELBIG, Lina BASEL-SALMON, Lior COHEN, Rachel STRAUSSBERG, Wendy K. CHUNG, Mayada HELAL, Reza MAROOFIAN, Henry HOULDEN, Jane JUUSOLA, Simon SADEDIN, Lynn PAIS, Katherine B. HOWELL, Susan M. WHITE, John CHRISTODOULOU and Mary Anne O'CONNELL (372 Ireland, guarantor, belonging to the institution)

Edition

The American Journal of Human Genetics, University of Chicago Press for the American Society of Human Genetics, 2020, 0002-9297

Other information

Language

English

Type of outcome

Článek v odborném periodiku

Field of Study

10608 Biochemistry and molecular biology

Country of publisher

United States of America

Confidentiality degree

není předmětem státního či obchodního tajemství

References:

URL

Impact factor

Impact factor: 11.025

RIV identification code

RIV/00216224:14740/20:00114081

Organization unit

Central European Institute of Technology

DOI

http://dx.doi.org/10.1016/j.ajhg.2020.02.015

UT WoS

000523306000005

Keywords in English

ADAR2; microcephaly; migrating focal seizures; epilepsy; intellectual disability; RNA editing

Abstract

V originále

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.

Links

GA19-16963S, research and development project

Name: Genetický model myši pro studium kontroly interferonu a zánětu

Investor: Czech Science Foundation

90062, large research infrastructures

Name: Czech-BioImaging

Citovat

TAN, Tiong Yang, Jiří SEDMÍK, Mark P. FITZGERALD, Rivka SUKENIK HALEVY, Liam KEEGAN, Ingo HELBIG, Lina BASEL-SALMON, Lior COHEN, Rachel STRAUSSBERG, Wendy K. CHUNG, Mayada HELAL, Reza MAROOFIAN, Henry HOULDEN, Jane JUUSOLA, Simon SADEDIN, Lynn PAIS, Katherine B. HOWELL, Susan M. WHITE, John CHRISTODOULOU and Mary Anne O'CONNELL. Bi-allelic ADARB1 Variants Associated with Microcephaly, Intellectual Disability, and Seizures. The American Journal of Human Genetics. University of Chicago Press for the American Society of Human Genetics, 2020, vol. 106, No 4, p. 467-483. ISSN 0002-9297. Available from: https://dx.doi.org/10.1016/j.ajhg.2020.02.015.

@article{1639636,
   author = {Tan, Tiong Yang and Sedmík, Jiří and Fitzgerald, Mark P. and Sukenik Halevy, Rivka and Keegan, Liam and Helbig, Ingo and BaselandSalmon, Lina and Cohen, Lior and Straussberg, Rachel and Chung, Wendy K. and Helal, Mayada and Maroofian, Reza and Houlden, Henry and Juusola, Jane and Sadedin, Simon and Pais, Lynn and Howell, Katherine B. and White, Susan M. and Christodoulou, John and O'Connell, Mary Anne},
   article_number = {4},
   doi = {http://dx.doi.org/10.1016/j.ajhg.2020.02.015},
   keywords = {ADAR2; microcephaly; migrating focal seizures; epilepsy; intellectual disability; RNA editing},
   language = {eng},
   issn = {0002-9297},
   journal = {The American Journal of Human Genetics},
   title = {Bi-allelic ADARB1 Variants Associated with Microcephaly, Intellectual Disability, and Seizures},
   url = {https://www.cell.com/ajhg/pdf/S0002-9297(20)30057-4.pdf},
   volume = {106},
   year = {2020}
}

TY  - JOUR
ID  - 1639636
AU  - Tan, Tiong Yang - Sedmík, Jiří - Fitzgerald, Mark P. - Sukenik Halevy, Rivka - Keegan, Liam - Helbig, Ingo - Basel-Salmon, Lina - Cohen, Lior - Straussberg, Rachel - Chung, Wendy K. - Helal, Mayada - Maroofian, Reza - Houlden, Henry - Juusola, Jane - Sadedin, Simon - Pais, Lynn - Howell, Katherine B. - White, Susan M. - Christodoulou, John - O'Connell, Mary Anne
PY  - 2020
TI  - Bi-allelic ADARB1 Variants Associated with Microcephaly, Intellectual Disability, and Seizures
JF  - The American Journal of Human Genetics
VL  - 106
IS  - 4
SP  - 467-483
EP  - 467-483
PB  - University of Chicago Press for the American Society of Human Genetics
SN  - 00029297
KW  - ADAR2
KW  - microcephaly
KW  - migrating focal seizures
KW  - epilepsy
KW  - intellectual disability
KW  - RNA editing
UR  - https://www.cell.com/ajhg/pdf/S0002-9297(20)30057-4.pdf
N2  - 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.
ER  -

TAN, Tiong Yang, Jiří SEDMÍK, Mark P. FITZGERALD, Rivka SUKENIK HALEVY, Liam KEEGAN, Ingo HELBIG, Lina BASEL-SALMON, Lior COHEN, Rachel STRAUSSBERG, Wendy K. CHUNG, Mayada HELAL, Reza MAROOFIAN, Henry HOULDEN, Jane JUUSOLA, Simon SADEDIN, Lynn PAIS, Katherine B. HOWELL, Susan M. WHITE, John CHRISTODOULOU and Mary Anne O'CONNELL. Bi-allelic ADARB1 Variants Associated with Microcephaly, Intellectual Disability, and Seizures. \textit{The American Journal of Human Genetics}. University of Chicago Press for the American Society of Human Genetics, 2020, vol.~106, No~4, p.~467-483. ISSN~0002-9297. Available from: https://dx.doi.org/10.1016/j.ajhg.2020.02.015.

Detailed Information on Publication Record