TY - JOUR
T1 - A missense variant in the nuclear export signal of the FMR1 gene causes intellectual disability
AU - Zeidler, Shimriet
AU - Severijnen, Lies-anne
AU - Boer, Helen
AU - van der Toorn, Esmay
AU - Ruivenkamp, CAL
AU - Bijlsma, EK
AU - Willemsen, Rob
N1 - Publisher Copyright:
© 2020
PY - 2021/2/5
Y1 - 2021/2/5
N2 - Fragile X syndrome (FXS) is the most common monogenetic cause of intellectual disability and autism spectrum disorders. Mostly, FXS is caused by transcriptional silencing of the FMR1 gene due to a repeat expansion in the 5′ UTR, and consequently lack of the protein product FMRP. However, in rare cases FXS is caused by other types of variants in the FMR1 gene. We describe a missense variant in the FMR1 gene, identified through whole-exome sequencing, in a boy with intellectual disability and behavioral problems. The variant is located in the FMRP's nuclear export signal (NES). We performed expression and localization studies of the variant in hair roots and HEK293 cells. Our results show normal expression but significant retention of the FMRP in the cells’ nucleus. This finding suggests a possible FMRP reduction at its essential functional sites in the dendrites and the synaptic compartments and possible interference of other cellular processes in the nucleus. Together, this might lead to a FXS phenotype in the boy.
AB - Fragile X syndrome (FXS) is the most common monogenetic cause of intellectual disability and autism spectrum disorders. Mostly, FXS is caused by transcriptional silencing of the FMR1 gene due to a repeat expansion in the 5′ UTR, and consequently lack of the protein product FMRP. However, in rare cases FXS is caused by other types of variants in the FMR1 gene. We describe a missense variant in the FMR1 gene, identified through whole-exome sequencing, in a boy with intellectual disability and behavioral problems. The variant is located in the FMRP's nuclear export signal (NES). We performed expression and localization studies of the variant in hair roots and HEK293 cells. Our results show normal expression but significant retention of the FMRP in the cells’ nucleus. This finding suggests a possible FMRP reduction at its essential functional sites in the dendrites and the synaptic compartments and possible interference of other cellular processes in the nucleus. Together, this might lead to a FXS phenotype in the boy.
UR - http://www.scopus.com/inward/record.url?scp=85096168562&partnerID=8YFLogxK
U2 - 10.1016/j.gene.2020.145298
DO - 10.1016/j.gene.2020.145298
M3 - Article
C2 - 33181255
SN - 0378-1119
VL - 768
JO - Gene
JF - Gene
M1 - 145298
ER -