Dataset Information

Significantly Elevated FMR1 mRNA and Mosaicism for Methylated Premutation and Full Mutation Alleles in Two Brothers with Autism Features Referred for Fragile X Testing.

ABSTRACT: Although fragile X syndrome (FXS) is caused by a hypermethylated full mutation (FM) expansion with ?200 cytosine-guanine-guanine (CGG) repeats, and a decrease in FMR1 mRNA and its protein (FMRP), incomplete silencing has been associated with more severe autism features in FXS males. This study reports on brothers (B1 and B2), aged 5 and 2 years, with autistic features and language delay, but a higher non-verbal IQ in comparison to typical FXS. CGG sizing using AmplideX PCR only identified premutation (PM: 55-199 CGGs) alleles in blood. Similarly, follow-up in B1 only revealed PM alleles in saliva and skin fibroblasts; whereas, an FM expansion was detected in both saliva and buccal DNA of B2. While Southern blot analysis of blood detected an unmethylated FM, methylation analysis with a more sensitive methodology showed that B1 had partially methylated PM alleles in blood and fibroblasts, which were completely unmethylated in buccal and saliva cells. In contrast, B2 was partially methylated in all tested tissues. Moreover, both brothers had FMR1 mRNA ~5 fold higher values than those of controls, FXS and PM cohorts. In conclusion, the presence of unmethylated FM and/or PM in both brothers may lead to an overexpression of toxic expanded mRNA in some cells, which may contribute to neurodevelopmental problems, including elevated autism features.

SUBMITTER: Field M

PROVIDER: S-EPMC6721168 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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Significantly Elevated <i>FMR1</i> mRNA and Mosaicism for Methylated Premutation and Full Mutation Alleles in Two Brothers with Autism Features Referred for Fragile X Testing.

Field Michael M Dudding-Byth Tracy T Arpone Marta M Baker Emma K EK Aliaga Solange M SM Rogers Carolyn C Hickerton Chriselle C Francis David D Phelan Dean G DG Palmer Elizabeth E EE Amor David J DJ Slater Howard H Bretherton Lesley L Ling Ling L Godler David E DE

International journal of molecular sciences 20190811 16

Although fragile X syndrome (FXS) is caused by a hypermethylated full mutation (FM) expansion with ≥200 cytosine-guanine-guanine (CGG) repeats, and a decrease in <i>FMR1</i> mRNA and its protein (FMRP), incomplete silencing has been associated with more severe autism features in FXS males. This study reports on brothers (B1 and B2), aged 5 and 2 years, with autistic features and language delay, but a higher non-verbal IQ in comparison to typical FXS. CGG sizing using AmplideX PCR only identified ...[more]

PMID: 31405222

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Project description:Individuals with the fragile X premutation express expanded CGG repeats (repeats 55-200) in the FMR1 gene and elevated FMR1 messenger RNA (mRNA) levels, both of which may underlie the occurrence of the late-onset neurodegenerative disorder fragile X-associated tremor/ataxia syndrome (FXTAS). Because the core feature of FXTAS is motor impairment, determining the influence of FMR1 mRNA levels on structural connectivity of motor fiber tracts is critical for a better understanding of the pathologic features of FXTAS.To examine the associations of CGG repeat and FMR1 mRNA with motor-related fiber tracts in males with premutation alleles.A case-control study conducted at the University of California, Davis, from April 1, 2008, through August 31, 2009. All data were collected masked to the carrier status of the FMR1 gene.Thirty-six male premutation carriers with FXTAS and 26 male premutation carriers without FXTAS were recruited through their family relationships with children affected by fragile X syndrome. The controls were 34 unaffected family members and healthy volunteers from the local community.The CGG repeat lengths and FMR1 mRNA expression levels in peripheral blood lymphocytes, motor functioning, and white matter structural integrity that were estimated using diffusion tensor imaging. After data collection, we selected 4 motor tracts to reconstruct using diffusion tensor tractography, namely, the middle and superior cerebellar peduncles, descending motor tracts (containing the corticospinal, corticobulbar, and corticopontine tracts), and the anterior body of the corpus callosum.All fiber tracts exhibited weaker structural connectivity in the FXTAS group (decreased 5%-53% from controls, P ? .02). Genetic imaging correlation analysis revealed negative associations of CGG repeat length and FMR1 mRNA with connectivity strength of the superior cerebellar peduncles in both premutation groups (partial r² = 0.23-0.33, P ? .004). In addition, the measurements from the corpus callosum and superior cerebellar peduncles revealed a high correlation with motor functioning in all 3 groups (r between partial least square predicted and actual test scores = 0.41-0.56, P ? .04).Distinct pathophysiologic processes may underlie the structural impairment of the motor tracts in FXTAS. Although both the corpus callosum and superior cerebellar peduncles were of great importance to motor functioning, only the superior cerebellar peduncles exhibited an association with the elevated RNA levels in the blood of fragile X premutation carriers.

Dataset Information

Significantly Elevated FMR1 mRNA and Mosaicism for Methylated Premutation and Full Mutation Alleles in Two Brothers with Autism Features Referred for Fragile X Testing.

Publications

Significantly Elevated <i>FMR1</i> mRNA and Mosaicism for Methylated Premutation and Full Mutation Alleles in Two Brothers with Autism Features Referred for Fragile X Testing.

Similar Datasets

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