AGG Triplets in FMR1 Linked to Number of CGG Repeats, Consanguinity, Study Finds

AGG Triplets in FMR1 Linked to Number of CGG Repeats, Consanguinity, Study Finds

The presence of AGG triplets in the FMR1 gene sequence may be linked to the number of CGG repeats — the genetic cause underlying fragile X syndrome — and the degree of consanguinity among individuals from the general population, according to a study.

The results of the study, “The role of AGG interruptions in the FMR1 gene stability: A survey in ethnic groups with low and high rate of consanguinity,” were published in Molecular Genetics & Genomic Medicine.

Fragile X syndrome (FXS), the most frequent single genetic cause of autism spectrum disorder (ASD), is caused by the expansion of CGG repeats in the fragile X mental retardation 1 (FMR1) gene, which provides instructions for making a protein called the fragile X mental retardation protein, or FMRP. Each CGG triplet has the instructions to produce an amino acid (the building blocks of proteins) called glutamine.

While full mutation carriers typically have more than 200 CGG repeats, pre-mutation carriers have between 55 and 200 CGG repeats. Healthy individuals have fewer than 57 CGG repeats.

Besides having CGG repeats, the FMR1 gene sequence typically also has AGG triplets that tend to appear in between every nine or 10 CGG repeats.

“It has been demonstrated that, in addition to the CGG repeat number, increased [FMR1 genetic] instability correlates with AGG loss,” the researchers stated. However, they said, “the prevalence and the role of AGG interruptions within the FMR1 gene in the [general] population is unknown.”

In this study, investigators from Israel’s Ben-Gurion University in collaboration with researchers from the University of California, Davis set out to explore the impact of the AGG triplets on the stability of the FMR1 gene in individuals from the general population with different levels of consanguinity.

The study involved 6,865 Bedouin women whose levels of consanguinity are estimated to range from 45.2% to 70.1% because of the high frequency of marriages between genetically related individuals within the community, and 6,204 Jewish women whose levels of consanguinity are estimated to be lower than 5%.

Investigators isolated DNA from blood samples collected from all the study participants. Genetic analyses were then used to assess the number of CGG repeats, as well as the presence of AGG triplets in the FMR1 gene sequence of all the women.

As expected, the homozygosity rate, more commonly known as inbreeding (breeding of genetically related individuals that leads to a decrease of genetic variability in the offspring), was higher among Bedouin women than among Jewish women.

Results showed that Jewish women tended to have a higher number of CGG repeats compared to Bedouin women:

  • The prevalence of pre-mutation carriers among Bedouin women was 1:158; among Jewish women, 1:128;
  • None of the Bedouin women carried the full FMR1 mutation; however, the prevalence of full mutation carriers among Jewish women was 1:1,149.

Genetic analyses also showed that Jewish women tended to have a higher number of AGG triplets than Bedouin women. Nevertheless, the loss of AGG triplets in between CGG repeats was relatively high among women from both groups, affecting 37.2% of Bedouin women and 32.2% of Jewish women.

In addition, investigators found that the loss of AGG triplets was directly correlated with the number of CGG repeats in women from both ethnic groups.

“[Our] results demonstrate that consanguinity affects the homozygosity as well as the prevalence of AGG loss. However, it did not affect the prevalence of the pre-mutation and full mutation of the FMR1 gene in the [high consanguinity] group.

“[Further] studies are warranted to clarify these results as well as the mechanism of FMR1 instability, which is, to date, still not fully understood.”

Joana holds a BSc in Biology and a MSc in Evolutionary and Developmental Biology from Universidade de Lisboa. She is currently finishing her PhD in Biomedicine and Clinical Research at Universidade de Lisboa. Her work has been focused on the impact of non-canonical Wnt signaling in the collective behavior of endothelial cells — cells that made up the lining of blood vessels — found in the umbilical cord of newborns.
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Joana holds a BSc in Biology and a MSc in Evolutionary and Developmental Biology from Universidade de Lisboa. She is currently finishing her PhD in Biomedicine and Clinical Research at Universidade de Lisboa. Her work has been focused on the impact of non-canonical Wnt signaling in the collective behavior of endothelial cells — cells that made up the lining of blood vessels — found in the umbilical cord of newborns.
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