Cis-acting DNA sequence at a replication origin promotes repeat expansion to fragile X full mutation
Jeannine Gerhardt1, Nikica Zaninovic2, Qiansheng Zhan2
1Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461 jeannine.gerhardt@gmail.com carl.schildkraut@einstein.yu.edu.
The Journal of Cell Biology
|September 3, 2014
Summary
Fragile X syndrome (FXS) may stem from a specific genetic variant near a replication origin. This variant
Area of Science:
- Genetics and Molecular Biology
- Developmental Biology
- Epigenetics
Background:
- Fragile X syndrome (FXS) is a genetic disorder caused by CGG repeat expansion in the FMR1 gene, leading to FMR1 gene silencing.
- Women carrying a premutation allele face an increased risk of transmitting a full mutation to their offspring, resulting in FXS.
- Understanding the molecular mechanisms driving CGG repeat expansion is crucial for developing targeted therapies.
Purpose of the Study:
- To investigate the relationship between a single-nucleotide polymorphism (SNP) variant and CGG repeat expansion in the context of Fragile X syndrome.
- To explore the role of a replication origin located upstream of the CGG repeats in the pathogenesis of FXS.
- To determine how genetic variations within replication origins influence repeat expansion dynamics.
Main Methods:
- Examined the association between a specific SNP variant (haplogroup D) and CGG repeat expansion.
- Investigated the presence and function of a replication origin approximately 53 kb upstream of the FMR1 CGG repeats.
- Compared replication origin status and SNP variants in Fragile X syndrome human embryonic stem cells (hESCs) versus nonaffected hESCs.
Main Results:
- The replication origin was absent in FXS hESCs, which carried the 'C' variant of the SNP.
- Nonaffected hESCs possessed the replication origin and harbored the 'T' variant of the SNP, which mapped directly within the origin.
- Premutation hESCs exhibited a replication origin and the 'T' variant, similar to nonaffected cells.
Conclusions:
- A T/C SNP within a replication origin may contribute to the inactivation of this origin in FXS hESCs.
- Inactivation of the replication origin could alter replication fork progression, promoting CGG repeat expansion to the full mutation.
- This study highlights a potential genetic mechanism linking replication origin function to Fragile X syndrome pathogenesis.
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