The molecular basis of the folate-sensitive fragile site FRA11A at 11q13

Debacker, Kim; Winnepenninckx, Birgitta; Longman, Cheryl; Colgan, J; Tolmie, J L; Murray, Ronald S.; Luijk, Rob van; Scheers, Stefaan; FitzPatrick, David R.; Kooy, R. Frank

doi:10.1159/000109612

Cited by 26 publications

(19 citation statements)

References 31 publications

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“…D). This is consistent with the local transcriptional repression associated with FRAXA [Oberle et al., ] and other reported FSFS [Debacker et al., ; Winnepenninckx et al., ; Metsu et al., ].…”

supporting

confidence: 91%

A CGG-Repeat Expansion Mutation inZNF713Causes FRA7A: Association with Autistic Spectrum Disorder in two Families

et al. 2014

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We report de novo occurrence of the 7p11.2 folate-sensitive fragile site FRA7A in a male with an autistic spectrum disorder (ASD) due to a CGG-repeat expansion mutation (∼450 repeats) in a 5' intron of ZNF713. This expanded allele showed hypermethylation of the adjacent CpG island with reduced ZNF713 expression observed in a proband-derived lymphoblastoid cell line (LCL). His unaffected mother carried an unmethylated premutation (85 repeats). This CGG-repeat showed length polymorphism in control samples (five to 22 repeats). In a second unrelated family, three siblings with ASD and their unaffected father were found to carry FRA7A premutations, which were partially or mosaically methylated. In one of the affected siblings, mitotic instability of the premutation was observed. ZNF713 expression in LCLs in this family was increased in three of these four premutation carriers. A firm link cannot yet be established between ASD and the repeat expansion mutation but plausible pathogenic mechanisms are discussed.

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supporting

confidence: 91%

A CGG-Repeat Expansion Mutation inZNF713Causes FRA7A: Association with Autistic Spectrum Disorder in two Families

et al. 2014

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“…Therefore, our results indicate that the deletion sequences identified here most likely represent a common fragile site. This is further strengthened by the report that the rare fragile site FRA11A is caused by expansion of a CCG repeat in the 5' end of the C11orf80 gene, located 660kb telomeric from D11S913 [39]. Further, loss of heterozygosity studies has identified a number of tumor suppressor genes at chromosome 11q13.1 [40–43].…”

Section: Discussionmentioning

confidence: 99%

One in four individuals of African-American ancestry harbors a 5.5 kb deletion at chromosome 11q13.1

et al. 2014

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Cloning and sequencing of 5.5kb deletion at chromosome 11q13.1 from the HeLa cells, tumorigenic hybrids and two fibroblast cell lines has revealed homologous recombination between AluSx and AluY resulting in the deletion of intervening sequences. Long-range PCR of the 5.5kb sequence in 494 normal lymphocyte samples showed heterozygous deletion in 28.3% of African- American ancestry samples but only in 4.8% of Caucasian samples (p<0.0001). This observation is strengthened by the copy number variation (CNV) data of the HapMap samples which showed that this deletion occurs in 27% of YRI (Yoruba – West African) population but none in non-African populations. The HapMap analysis further identified strong linkage disequilibrium between 5 single nucleotide polymorphisms and the 5.5kb deletion in the people of African ancestry. Computational analysis of 175kb sequence surrounding the deletion site revealed enhanced flexibility, low thermodynamic stability, high repetitiveness, and stable stem-loop/hairpin secondary structures that are hallmarks of common fragile sites.

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“…FRAXA is a rare, folate sensitive fragile site (FSFS) associated with a trinucleotide repeat (CGG) expansion mutation in the 5′ UTR of the FMR1 gene resulting in fragile X syndrome, the most common inherited intellectual disability syndrome [20]. Twenty-six other FSFS have been reported cytogenetically but only eight of these have been molecularly characterized: FRAXA [20], FRAXE [21], FRAXF [22], FRA16A [23], FRA11B [24], FRA10A [25], FRA12A [26] and FRA11A [27]. To date, all characterized FSFS are due to a CCG/CGG trinucleotide repeat expansion.…”

Section: Introductionmentioning

confidence: 99%

FRA2A Is a CGG Repeat Expansion Associated with Silencing of AFF3

et al. 2014

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Folate-sensitive fragile sites (FSFS) are a rare cytogenetically visible subset of dynamic mutations. Of the eight molecularly characterized FSFS, four are associated with intellectual disability (ID). Cytogenetic expression results from CGG tri-nucleotide-repeat expansion mutation associated with local CpG hypermethylation and transcriptional silencing. The best studied is the FRAXA site in the FMR1 gene, where large expansions cause fragile X syndrome, the most common inherited ID syndrome. Here we studied three families with FRA2A expression at 2q11 associated with a wide spectrum of neurodevelopmental phenotypes. We identified a polymorphic CGG repeat in a conserved, brain-active alternative promoter of the AFF3 gene, an autosomal homolog of the X-linked AFF2/FMR2 gene: Expansion of the AFF2 CGG repeat causes FRAXE ID. We found that FRA2A-expressing individuals have mosaic expansions of the AFF3 CGG repeat in the range of several hundred repeat units. Moreover, bisulfite sequencing and pyrosequencing both suggest AFF3 promoter hypermethylation. cSNP-analysis demonstrates monoallelic expression of the AFF3 gene in FRA2A carriers thus predicting that FRA2A expression results in functional haploinsufficiency for AFF3 at least in a subset of tissues. By whole-mount in situ hybridization the mouse AFF3 ortholog shows strong regional expression in the developing brain, somites and limb buds in 9.5–12.5dpc mouse embryos. Our data suggest that there may be an association between FRA2A and a delay in the acquisition of motor and language skills in the families studied here. However, additional cases are required to firmly establish a causal relationship.

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The molecular basis of the folate-sensitive fragile site FRA11A at 11q13

Cited by 26 publications

References 31 publications

A CGG-Repeat Expansion Mutation inZNF713Causes FRA7A: Association with Autistic Spectrum Disorder in two Families

A CGG-Repeat Expansion Mutation inZNF713Causes FRA7A: Association with Autistic Spectrum Disorder in two Families

One in four individuals of African-American ancestry harbors a 5.5 kb deletion at chromosome 11q13.1

FRA2A Is a CGG Repeat Expansion Associated with Silencing of AFF3

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