Fragile X full mutations are more similar in siblings than in unrelated patients: further evidence for a familial factor in CGG repeat dynamics

AbstractCGG tandem repeat expansion in the 5′-untranslated region of the fragile X mental retardation-1 (FMR1) gene leads to unusual nucleic acid conformations, hence causing genetic instabilities. We show that the number of G…G (in CGG repeat) or C…C (in CCG repeat) mismatches (other than A…T, T…A, C…G and G…C canonical base pairs) dictates the secondary structural choice of the sense and antisense strands of the FMR1 gene and their corresponding transcripts in fragile X-associated tremor/ataxia syndrome (FXTAS). The circular dichroism (CD) spectra and electrophoretic mobility shift assay (EMSA) reveal that CGG DNA (sense strand of the FMR1 gene) and its transcript favor a quadruplex structure. CD, EMSA and molecular dynamics (MD) simulations also show that more than four C…C mismatches cannot be accommodated in the RNA duplex consisting of the CCG repeat (antisense transcript); instead, it favors an i-motif conformational intermediate. Such a preference for unusual secondary structures provides a convincing justification for the RNA foci formation due to the sequestration of RNA-binding proteins to the bidirectional transcripts and the repeat-associated non-AUG translation that are observed in FXTAS. The results presented here also suggest that small molecule modulators that can destabilize FMR1 CGG DNA and RNA quadruplex structures could be promising candidates for treating FXTAS.

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Autism Profiles of Males With Fragile X Syndrome

American Journal on Mental Retardation ◽

10.1352/2008.113:427-438 ◽

2008 ◽

Vol 113 (6) ◽

pp. 427-438 ◽

Cited By ~ 251

Author(s):

Susan W. Harris ◽

David Hessl ◽

Beth Goodlin-Jones ◽

Jessica Ferranti ◽

Susan Bacalman ◽

...

Keyword(s):

Fragile X Syndrome ◽

Fragile X ◽

Autism Diagnosis ◽

Cgg Repeat ◽

Molecular Features ◽

Fmr1 Mrna ◽

Two Measures ◽

Dsm Iv ◽

Relationship Of ◽

The Relationship

Abstract Autism, which is common in individuals with fragile X syndrome, is often difficult to diagnose. We compared the diagnostic classifications of two measures for autism diagnosis, the ADOS and the ADI-R, in addition to the DSM-IV-TR in 63 males with this syndrome. Overall, 30% of the subjects met criteria for autistic disorder and 30% met criteria for PDD-NOS. The classifications on the ADOS and DSM-IV-TR were most similar, whereas the ADI-R classified subjects as autistic much more frequently. We further investigated the relationship of both FMRP and FMR1 mRNA to symptoms of autism in this cohort and found no significant relationship between the measures of autism and molecular features, including FMRP, FMR1 mRNA, and CGG repeat number.

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CGG repeat length correlates with age of onset of motor signs of the fragile X-associated tremor/ataxia syndrome (FXTAS)

American Journal of Medical Genetics Part B Neuropsychiatric Genetics ◽

10.1002/ajmg.b.30482 ◽

2007 ◽

Vol 144B (4) ◽

pp. 566-569 ◽

Cited By ~ 95

Author(s):

Flora Tassone ◽

John Adams ◽

Elizabeth M. Berry-Kravis ◽

Susannah S. Cohen ◽

Alfredo Brusco ◽

...

Keyword(s):

Age Of Onset ◽

Fragile X ◽

Repeat Length ◽

Cgg Repeat ◽

Ataxia Syndrome

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ASFMR1splice variant

Neurology Genetics ◽

10.1212/nxg.0000000000000246 ◽

2018 ◽

Vol 4 (4) ◽

pp. e246 ◽

Cited By ~ 6

Author(s):

Padmaja Vittal ◽

Shrikant Pandya ◽

Kevin Sharp ◽

Elizabeth Berry-Kravis ◽

Lili Zhou ◽

...

Keyword(s):

Mental Retardation ◽

Splice Variant ◽

Messenger Rna ◽

Clinical Symptoms ◽

Fragile X ◽

Cgg Repeat ◽

Men And Women ◽

Fragile X Mental Retardation ◽

Repeat Size ◽

Ataxia Syndrome

ObjectiveTo explore the association of a splice variant of theantisense fragile X mental retardation 1(ASFMR1) gene, loss offragile X mental retardation 1(FMR1) AGG interspersions andFMR1CGG repeat size with manifestation, and severity of clinical symptoms of fragile X-associated tremor/ataxia syndrome (FXTAS).MethodsPremutation carriers (PMCs) with FXTAS, without FXTAS, and normal controls (NCs) had a neurologic evaluation and collection of skin and blood samples. Expression ofASFMR1transcript/splice variant 2 (ASFMR1-TV2), nonsplicedASFMR1, totalASFMR1, andFMR1messenger RNA were quantified and compared using analysis of variance. Least absolute shrinkage and selection operator (LASSO) logistic regression and receiver operating characteristic analyses were performed.ResultsPremutation men and women both with and without FXTAS had higherASFMR1-TV2 levels compared with NC men and women (n = 135,135,p< 0.0001), andASFMR1-TV2 had good discriminating power for FXTAS compared with NCs but not for FXTAS from PMC. After adjusting for age, loss of AGG, larger CGG repeat size (in men), and elevatedASFMR1-TV2 level (in women) were strongly associated with FXTAS compared with NC and PMC (combined).ConclusionsThis study found elevated levels ofASFMR1-TV2and loss of AGG interruptions in both men and women with FXTAS. Future studies will be needed to determine whether these variables can provide useful diagnostic or predictive information.

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Learning-disabled Males With a Fragile X CGG Expansion in the Upper Premutation Size Range

PEDIATRICS ◽

10.1542/peds.97.1.122 ◽

1996 ◽

Vol 97 (1) ◽

pp. 122-126

Author(s):

Randi J. Hagerman ◽

Louise W. Staley ◽

Rebecca O'Conner ◽

Kellie Lugenbeel ◽

David Nelson ◽

...

Keyword(s):

Mental Retardation ◽

Fragile X Syndrome ◽

Size Range ◽

Cpg Island ◽

Fragile X ◽

Learning Disabled ◽

Full Mutation ◽

Cgg Repeat ◽

Responsible Gene ◽

Repeat Segment

There is a broad spectrum of clinical involvement in both boys and girls affected by fragile X syndrome. Although this disorder is best known as the most common inherited cause of mental retardation, it also can manifest as learning disabilities in individuals with IQs in the broad range of normal. Boys are usually retarded, and girls are usually learning disabled with fragile X syndrome.1 The responsible gene, fragile X mental retardation 1 (FMR1), was isolated in 1991, and the mutation was found to involve expansion of a trinucleotide (CGG) repeat segment. Individuals with fragile X syndrome have a CGG expansion of more than 200 repeats associated with hypermethylation of both the expansion and an adjacent CpG island (full mutation).2,3

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