MeCP2_e2 partially compensates for lack of MeCP2_e1: A male case of Rett syndrome.
MeCP2 isoform
MeCP2_e1
MeCP2_e2
male with Rett syndrome
somatic mosaicism
Journal
Molecular genetics & genomic medicine
ISSN: 2324-9269
Titre abrégé: Mol Genet Genomic Med
Pays: United States
ID NLM: 101603758
Informations de publication
Date de publication:
02 2020
02 2020
Historique:
received:
19
08
2019
revised:
12
11
2019
accepted:
13
11
2019
pubmed:
10
12
2019
medline:
27
3
2021
entrez:
10
12
2019
Statut:
ppublish
Résumé
Rett syndrome (RTT) is a neurodevelopmental disorder that predominantly affects girls. Its causative gene is the X-linked MECP2 encoding the methyl-CpG-binding protein 2 (MeCP2). The gene comprises four exons and generates two isoforms, namely MECP2_e1 and MECP2_e2. However, it remains unclear whether both MeCP2 isoforms have similar function in the brain. We report a case of a boy with typical RTT. Male cases with MECP2 variants have been considered inviable, but somatic mosaicism of the variants can cause RTT in males. Whole-exome sequencing was performed to search for the genetic background. A novel nonsense and mosaic variant was identified in exon 1 of MECP2, and the variant allele fraction (VAF) was 28%. Our patient had the same level of VAF as that in reported male cases with mosaic variants in MECP2 exon 3 or 4, but manifested RTT symptoms that were milder in severity compared to those in these patients. This is probably because the variants in MECP2 exon 3 or 4 disrupt both isoforms of MeCP2, whereas the variant in exon 1, as presented in this study, disrupts only MeCP2_e1 but not MeCP2_e2. Therefore, our findings indicate that MeCP2_e2 may partially compensate for a deficiency in MeCP2_e1.
Sections du résumé
BACKGROUND
Rett syndrome (RTT) is a neurodevelopmental disorder that predominantly affects girls. Its causative gene is the X-linked MECP2 encoding the methyl-CpG-binding protein 2 (MeCP2). The gene comprises four exons and generates two isoforms, namely MECP2_e1 and MECP2_e2. However, it remains unclear whether both MeCP2 isoforms have similar function in the brain.
METHODS
We report a case of a boy with typical RTT. Male cases with MECP2 variants have been considered inviable, but somatic mosaicism of the variants can cause RTT in males. Whole-exome sequencing was performed to search for the genetic background.
RESULTS
A novel nonsense and mosaic variant was identified in exon 1 of MECP2, and the variant allele fraction (VAF) was 28%. Our patient had the same level of VAF as that in reported male cases with mosaic variants in MECP2 exon 3 or 4, but manifested RTT symptoms that were milder in severity compared to those in these patients.
CONCLUSION
This is probably because the variants in MECP2 exon 3 or 4 disrupt both isoforms of MeCP2, whereas the variant in exon 1, as presented in this study, disrupts only MeCP2_e1 but not MeCP2_e2. Therefore, our findings indicate that MeCP2_e2 may partially compensate for a deficiency in MeCP2_e1.
Identifiants
pubmed: 31816669
doi: 10.1002/mgg3.1088
pmc: PMC7005616
doi:
Substances chimiques
MECP2 protein, human
0
Methyl-CpG-Binding Protein 2
0
Protein Isoforms
0
Types de publication
Case Reports
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
e1088Informations de copyright
© 2019 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc.
Références
Hum Mol Genet. 2014 May 1;23(9):2447-58
pubmed: 24352790
Ann Neurol. 2010 Dec;68(6):944-50
pubmed: 21154482
Am J Med Genet A. 2009 May;149A(5):1019-23
pubmed: 19365833
Clin Genet. 2019 Mar;95(3):403-408
pubmed: 30417326
Eur J Hum Genet. 2012 Jan;20(1):69-76
pubmed: 21829232
Neuropediatrics. 2001 Jun;32(3):162-4
pubmed: 11521215
Hum Mol Genet. 2008 May 15;17(10):1386-96
pubmed: 18223199
J Biol Chem. 2012 Apr 20;287(17):13859-67
pubmed: 22375006
RNA. 2008 Mar;14(3):563-76
pubmed: 18230761
Genet Med. 2019 Jun;21(6):1330-1338
pubmed: 30405208
Eur J Hum Genet. 2002 Jan;10(1):77-81
pubmed: 11896459
Brain Dev. 2018 Apr;40(4):259-267
pubmed: 29217415
Mol Genet Genomic Med. 2020 Feb;8(2):e1088
pubmed: 31816669
Eur J Hum Genet. 2004 Jan;12(1):24-8
pubmed: 14560307
Nat Genet. 2004 Apr;36(4):339-41
pubmed: 15034579
J Med Genet. 2007 Jul;44(7):417-23
pubmed: 17351020
Clin Genet. 2008 Mar;73(3):257-61
pubmed: 18190595