Loss of the KH1 domain of FMR1 in humans due to a synonymous variant causes global developmental retardation.
Adolescent
Adult
Alleles
Cohort Studies
Exons
Fragile X Mental Retardation Protein
/ genetics
Fragile X Syndrome
/ genetics
Humans
Intellectual Disability
/ genetics
Male
Mutation
Phenotype
Polymorphism, Single Nucleotide
Protein Domains
RNA Splicing
Sequence Analysis, RNA
/ methods
Silent Mutation
Trinucleotide Repeat Expansion
Exon skipping
FMR1
Fragile X syndrome
Synonymous variant
Journal
Gene
ISSN: 1879-0038
Titre abrégé: Gene
Pays: Netherlands
ID NLM: 7706761
Informations de publication
Date de publication:
30 Aug 2020
30 Aug 2020
Historique:
received:
19
03
2020
revised:
30
04
2020
accepted:
18
05
2020
pubmed:
25
5
2020
medline:
1
8
2020
entrez:
25
5
2020
Statut:
ppublish
Résumé
Fragile X syndrome (FXS) is a monogenic disorder and a common cause of intellectual disability (ID). Up to now, very few pathological variants other than the typical CGG-repeat expansion have been reported in the FMR1 gene. A panel of 56 intellectual disability (ID) genes including the FMR1 gene was sequenced in a cohort of 300 patients with unexplained ID. To determine the effect of a new FMR1 variant, total RNA from peripheral blood cells was reverse transcribed, amplified by polymerase chain reaction and sequenced. We report a novel G to A point variant (c.801G > A) located at the last nucleotide of exon 8 in the FMR1 gene in one patient with ID. Direct sequencing of the RT-PCR products revealed that the transcript from the allele with G to A variant skips exon 8 entirely, resulting in a joining of exons 7 and 9. Skipping of exon 8 may result in an abnormal FMR1 protein (FMRP), which removes the highly conserved region that encoding the KH1 domain of FMRP. This report describes for the first time that a synonymous variant in the FMR1 gene is associated with an error in mRNA processing, leading preferentially to the production of an aberrant transcript without exon 8. This splice variant was associated with an unspecific clinical presentation, suggesting the need for more detailed investigation of silent variants in ID patients with a large spectrum of phenotypes.
Sections du résumé
BACKGROUND
BACKGROUND
Fragile X syndrome (FXS) is a monogenic disorder and a common cause of intellectual disability (ID). Up to now, very few pathological variants other than the typical CGG-repeat expansion have been reported in the FMR1 gene.
METHODS
METHODS
A panel of 56 intellectual disability (ID) genes including the FMR1 gene was sequenced in a cohort of 300 patients with unexplained ID. To determine the effect of a new FMR1 variant, total RNA from peripheral blood cells was reverse transcribed, amplified by polymerase chain reaction and sequenced.
RESULTS
RESULTS
We report a novel G to A point variant (c.801G > A) located at the last nucleotide of exon 8 in the FMR1 gene in one patient with ID. Direct sequencing of the RT-PCR products revealed that the transcript from the allele with G to A variant skips exon 8 entirely, resulting in a joining of exons 7 and 9. Skipping of exon 8 may result in an abnormal FMR1 protein (FMRP), which removes the highly conserved region that encoding the KH1 domain of FMRP.
CONCLUSIONS
CONCLUSIONS
This report describes for the first time that a synonymous variant in the FMR1 gene is associated with an error in mRNA processing, leading preferentially to the production of an aberrant transcript without exon 8. This splice variant was associated with an unspecific clinical presentation, suggesting the need for more detailed investigation of silent variants in ID patients with a large spectrum of phenotypes.
Identifiants
pubmed: 32446918
pii: S0378-1119(20)30462-5
doi: 10.1016/j.gene.2020.144793
pii:
doi:
Substances chimiques
FMR1 protein, human
0
Fragile X Mental Retardation Protein
139135-51-6
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
144793Informations de copyright
Copyright © 2020 Elsevier B.V. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.