A non-coding variant in the Kozak sequence of RARS2 strongly decreases protein levels and causes pontocerebellar hypoplasia.
Bioinformatic predictions
Kozak
Non-coding variant
Pontocerebellar Hypoplasia
RARS2
Journal
BMC medical genomics
ISSN: 1755-8794
Titre abrégé: BMC Med Genomics
Pays: England
ID NLM: 101319628
Informations de publication
Date de publication:
21 06 2023
21 06 2023
Historique:
received:
21
10
2022
accepted:
16
06
2023
medline:
23
6
2023
pubmed:
22
6
2023
entrez:
21
6
2023
Statut:
epublish
Résumé
Bi-allelic variants in the mitochondrial arginyl-transfer RNA synthetase (RARS2) gene have been involved in early-onset encephalopathies classified as pontocerebellar hypoplasia (PCH) type 6 and in epileptic encephalopathy. A variant (NM_020320.3:c.-2A > G) in the promoter and 5'UTR of the RARS2 gene has been previously identified in a family with PCH. Only a mild impact of this variant on the mRNA level has been detected. As RARS2 is non-dosage-sensitive, this observation is not conclusive in regard of the pathogenicity of the variant.We report and describe here a new patient with the same variant in the RARS2 gene, at the homozygous state. This patient presents with a clinical phenotype consistent with PCH6 although in the absence of lactic acidosis. In agreement with the previous study, we measured RARS2 mRNA levels in patient's fibroblasts and detected a partially preserved gene expression compared to control. Importantly, this variant is located in the Kozak sequence that controls translation initiation. Therefore, we investigated the impact on protein translation using a bioinformatic approach and western blotting. We show here that this variant, additionally to its effect on the transcription, also disrupts the consensus Kozak sequence, and has a major impact on RARS2 protein translation. Through the identification of this additional case and the characterization of the molecular consequences, we clarified the involvement of this Kozak variant in PCH and on protein synthesis. This work also points to the current limitation in the pathogenicity prediction of variants located in the translation initiation region.
Identifiants
pubmed: 37344844
doi: 10.1186/s12920-023-01582-z
pii: 10.1186/s12920-023-01582-z
pmc: PMC10283289
doi:
Substances chimiques
RNA, Messenger
0
RARS2 protein, human
EC 6.1.1.19
Arginine-tRNA Ligase
EC 6.1.1.19
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
143Informations de copyright
© 2023. The Author(s).
Références
Hum Mol Genet. 2019 May 1;28(9):1548-1560
pubmed: 30624672
J Neurol Sci. 1990 Jun;97(1):25-42
pubmed: 2370559
BMC Res Notes. 2011 Aug 27;4:312
pubmed: 21871111
Front Genet. 2020 Sep 10;11:1033
pubmed: 33133137
JAMA Psychiatry. 2013 Jun;70(6):591-8
pubmed: 23575746
Cerebellum. 2021 Aug;20(4):631-658
pubmed: 33534089
Am J Hum Genet. 2010 Oct 8;87(4):538-44
pubmed: 20920667
Nat Methods. 2015 Oct;12(10):931-4
pubmed: 26301843
PLoS One. 2008 Aug 28;3(8):e3094
pubmed: 18769482
Mol Neurobiol. 2017 Jan;54(1):541-550
pubmed: 26742529
Nat Genet. 2008 Sep;40(9):1113-8
pubmed: 18711368
Cell. 2014 Apr 24;157(3):636-50
pubmed: 24766809
Eur J Med Genet. 2020 Mar;63(3):103766
pubmed: 31536827
Nucleic Acids Res. 1987 Oct 26;15(20):8125-48
pubmed: 3313277
J Inherit Metab Dis. 2013 Jan;36(1):43-53
pubmed: 22569581
Epilepsia Open. 2018 Mar 23;3(2):270-275
pubmed: 29881806
Nat Genet. 2019 May;51(5):772-776
pubmed: 30962618
Am J Med Genet A. 2014 Nov;164A(11):2732-8
pubmed: 25099673
Bioinformatics. 2017 Jul 15;33(14):i234-i242
pubmed: 28881981
J Hum Genet. 2015 Jul;60(7):363-9
pubmed: 25809939
Neuron. 2021 Jan 20;109(2):241-256.e9
pubmed: 33220177
Cell. 2004 Apr 30;117(3):311-21
pubmed: 15109492
Pediatr Neurol. 2022 Jun;131:30-41
pubmed: 35468344
Genome Biol. 2019 Feb 11;20(1):32
pubmed: 30744685
PLoS One. 2014 Sep 23;9(9):e108475
pubmed: 25248153
Cell. 2014 Apr 24;157(3):651-63
pubmed: 24766810
Nat Genet. 2012 Apr 29;44(6):704-8
pubmed: 22544365
Brain. 2018 Jul 1;141(7):1998-2013
pubmed: 29878067
JIMD Rep. 2017;33:87-92
pubmed: 27683254
Epilepsia Open. 2022 Mar;7(1):170-180
pubmed: 34717047
Cerebellum. 2020 Aug;19(4):569-582
pubmed: 32410094
Am J Hum Genet. 2007 Oct;81(4):857-62
pubmed: 17847012
Nat Genet. 2017 Mar;49(3):457-464
pubmed: 28092684
Nat Commun. 2014 Jul 03;5:4287
pubmed: 24989451
Stem Cell Rev Rep. 2021 Oct;17(5):1590-1606
pubmed: 33728560
Mol Syst Biol. 2014 Aug 28;10:748
pubmed: 25170020
Orphanet J Rare Dis. 2016 Oct 21;11(1):140
pubmed: 27769281
Oncotarget. 2016 Oct 25;7(43):69384-69396
pubmed: 27655721
Front Genet. 2021 Apr 08;12:607965
pubmed: 33897753
Brain Dev. 1993 Nov-Dec;15(6):411-22
pubmed: 8147499
Zhonghua Er Ke Za Zhi. 2020 Nov 2;58(11):893-899
pubmed: 33120460
Orphanet J Rare Dis. 2018 Jun 15;13(1):92
pubmed: 29903031
Br J Haematol. 2004 Jan;124(2):224-31
pubmed: 14687034
J Thromb Haemost. 2003 Dec;1(12):2688-9
pubmed: 14675111
Nat Commun. 2020 Nov 30;11(1):6087
pubmed: 33257696
BMC Neurol. 2021 Oct 2;21(1):382
pubmed: 34600502
Blood. 1999 Jul 1;94(1):186-91
pubmed: 10381512
JAMA Pediatr. 2021 May 1;175(5):e205906
pubmed: 33587123
J Inherit Metab Dis. 2012 May;35(3):459-67
pubmed: 22086604
Am J Hum Genet. 2018 May 3;102(5):858-873
pubmed: 29727687
Transl Pediatr. 2020 Oct;9(5):707-712
pubmed: 33209735
J Neuropathol Exp Neurol. 2015 Jul;74(7):688-703
pubmed: 26083569
Eur J Paediatr Neurol. 2016 May;20(3):412-7
pubmed: 26970947
J Am Coll Cardiol. 2001 Oct;38(4):1023-7
pubmed: 11583876
Exp Ther Med. 2018 Jan;15(1):1099-1104
pubmed: 29434700
Am J Hum Genet. 2022 May 5;109(5):909-927
pubmed: 35390279
Trends Biochem Sci. 2019 Dec;44(12):1009-1021
pubmed: 31353284