Cis-acting DNA sequence at a replication origin promotes repeat expansion to fragile X full mutation.
J Cell Biol
; 206(5): 599-607, 2014 Sep 01.
Article
em En
| MEDLINE
| ID: mdl-25179629
ABSTRACT
Fragile X syndrome (FXS) is caused by CGG repeat expansion that leads to FMR1 silencing. Women with a premutation allele are at risk of having a full mutation child with FXS. To investigate the mechanism of repeat expansion, we examined the relationship between a single-nucleotide polymorphism (SNP) variant that is linked to repeat expansion in haplogroup D and a replication origin located â¼53 kb upstream of the repeats. This origin is absent in FXS human embryonic stem cells (hESCs), which have the SNP variant C, but present in the nonaffected hESCs, which have a T variant. The SNP maps directly within the replication origin. Interestingly, premutation hESCs have a replication origin and the T variant similar to nonaffected hESCs. These results suggest that a T/C SNP located at a replication origin could contribute to the inactivation of this replication origin in FXS hESCs, leading to altered replication fork progression through the repeats, which could result in repeat expansion to the FXS full mutation.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Origem de Replicação
/
Expansão das Repetições de Trinucleotídeos
/
Síndrome do Cromossomo X Frágil
Limite:
Animals
/
Female
/
Humans
Idioma:
En
Revista:
J Cell Biol
Ano de publicação:
2014
Tipo de documento:
Article