Methylated premutation of the FMR1 gene in three sisters: correlating CGG expansion and epigenetic inactivation

Tabolacci, Elisabetta; Pomponi, Maria Grazia; Remondini, Laura; Pietrobono, Roberta; Nobile, Veronica; Pennacchio, Gaetana; Gurrieri, Fiorella; Neri, Giovanni; Genuardi, Maurizio; Chiurazzi, Pietro

doi:10.1038/s41431-019-0554-7

Cited by 7 publications

(2 citation statements)

References 35 publications

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“…It is also notable that PM alleles may be unstable and differ across tissue types [ 86 , 90 , 95 , 477 , 478 ], and the repeat size mosaicism of PM/full-mutation alleles is more likely to occur when the predominant PM CGG repeat length is at the upper end of the PM range [ 479 ]. This implies that the CGG expansion can be present at a larger size (e.g., a full mutation) in unmeasured tissues (including the brain).…”

Section: Screening For Fragile X and Fxpacmentioning

confidence: 99%

Insight and Recommendations for Fragile X-Premutation-Associated Conditions from the Fifth International Conference on FMR1 Premutation

Tassone,

Protic,

Allen

et al. 2023

Cells

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The premutation of the fragile X messenger ribonucleoprotein 1 (FMR1) gene is characterized by an expansion of the CGG trinucleotide repeats (55 to 200 CGGs) in the 5’ untranslated region and increased levels of FMR1 mRNA. Molecular mechanisms leading to fragile X-premutation-associated conditions (FXPAC) include cotranscriptional R-loop formations, FMR1 mRNA toxicity through both RNA gelation into nuclear foci and sequestration of various CGG-repeat-binding proteins, and the repeat-associated non-AUG (RAN)-initiated translation of potentially toxic proteins. Such molecular mechanisms contribute to subsequent consequences, including mitochondrial dysfunction and neuronal death. Clinically, premutation carriers may exhibit a wide range of symptoms and phenotypes. Any of the problems associated with the premutation can appropriately be called FXPAC. Fragile X-associated tremor/ataxia syndrome (FXTAS), fragile X-associated primary ovarian insufficiency (FXPOI), and fragile X-associated neuropsychiatric disorders (FXAND) can fall under FXPAC. Understanding the molecular and clinical aspects of the premutation of the FMR1 gene is crucial for the accurate diagnosis, genetic counseling, and appropriate management of affected individuals and families. This paper summarizes all the known problems associated with the premutation and documents the presentations and discussions that occurred at the International Premutation Conference, which took place in New Zealand in 2023.

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Section: Screening For Fragile X and Fxpacmentioning

confidence: 99%

Insight and Recommendations for Fragile X-Premutation-Associated Conditions from the Fifth International Conference on FMR1 Premutation

Tassone,

Protic,

Allen

et al. 2023

Cells

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show abstract

“…Owing to the presence of the second X chromosome with a healthy FMR1 gene in females, occasionally mild features are the only phenotypes that could be diagnosed in them even when they carry a pre-mutated or full-mutated FMR1 gene [ 13 , 14 ]. Recently Tabolacci et al presented several FXS patients with fully methylated pre-mutated alleles [ 15 ]. This epigenetic finding probably could be the main reason for the mild MR observed in females with the pre-mutated FMR1 gene.…”

Section: Discussionmentioning

confidence: 99%

Fragile X Syndrome in a Female With Homozygous Full-Mutation Alleles of the FMR1 Gene

Vafaeie¹,

Alerasool²,

Mojaver³

et al. 2021

Cureus

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Fragile X syndrome (FXS) has been reported as the leading cause of mental retardation (MR) that predominantly involves males compared to females. An over-expansion of CGG repeats in the 5′ untranslated region of the FMR1 gene plays the primary role in this disease. In this study, we encountered a homozygote female patient affected by FMR1 expansion mutation. Surprisingly, she had inherited her fullmutated alleles from two different ancestors. This condition is an extremely rare case of FXS. After accurate genetic counseling, family members were referred to the laboratory for genetic testing. Karyotype with two X chromosomes was the finding after the G-banding study of the proband.Molecular analysis indicated that she was a female with full-mutated or pre-mutated alleles on both of her X chromosomes. It is a rare phenomenon that we detected in this patient. We have concluded that a combination of allele instability during oogenesis and inheritance of two alleles are the leading cause of MR in the presented case.

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Ethnicity has a multiplex impact upon the risk of a full mutation expansion among female heterozygotes for FMR1 premutation

Domniz

Levavi

Berkenstadt

et al. 2021

Genetics in Medicine

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Methylated premutation of the FMR1 gene in three sisters: correlating CGG expansion and epigenetic inactivation

Cited by 7 publications

References 35 publications

Insight and Recommendations for Fragile X-Premutation-Associated Conditions from the Fifth International Conference on FMR1 Premutation

Insight and Recommendations for Fragile X-Premutation-Associated Conditions from the Fifth International Conference on FMR1 Premutation

Fragile X Syndrome in a Female With Homozygous Full-Mutation Alleles of the FMR1 Gene

Ethnicity has a multiplex impact upon the risk of a full mutation expansion among female heterozygotes for FMR1 premutation

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