FMR1 mRNA from full mutation alleles is associated with ABC-CFX scores in males with fragile X syndrome

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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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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Analysis of unstable DNA sequence in FMR1 gene in Polish families with fragile X syndrome.

Acta Biochimica Polonica ◽

10.18388/abp.1996_4508 ◽

1996 ◽

Vol 43 (2) ◽

pp. 383-388

Author(s):

M Milewski ◽

M Zygulska ◽

J Bal ◽

W H Deelen ◽

E Obersztyn ◽

...

Keyword(s):

Fragile X Syndrome ◽

Dna Sequence ◽

Clinical Features ◽

Fragile Site ◽

Fragile X ◽

Fmr1 Gene ◽

Repeat Number ◽

Full Mutation ◽

Cgg Repeats ◽

Large Expansion

The unstable DNA sequence in the FMR1 gene was analyzed in 85 individuals from Polish families with fragile X syndrome in order to characterize mutations responsible for the disease in Poland. In all affected individuals classified on the basis of clinical features and expression of the fragile site at X(q27.3) a large expansion of the unstable sequence (full mutation) was detected. About 5% (2 of 43) of individuals with full mutation did not express the fragile site. Among normal alleles, ranging in size from 20 to 41 CGG repeats, allele with 29 repeats was the most frequent (37%). Transmission of premutated and fully mutated alleles to the offspring was always associated with size increase. No change in repeat number was found when normal alleles were transmitted.

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Fragile X: A Family of Disorders

Cognitive and Behavioral Abnormalities of Pediatric Diseases ◽

10.1093/oso/9780195342680.003.0024 ◽

2010 ◽

Author(s):

Ann M. Mastergeorge ◽

Jacky Au

Keyword(s):

Intellectual Disability ◽

Fragile X Syndrome ◽

X Chromosome ◽

Culture Media ◽

Fragile Site ◽

Fragile X ◽

Single Gene ◽

Repeat Sequence ◽

Full Mutation ◽

Tissue Culture Media

Fragile X syndrome (FXS) is the most common cause of inherited intellectual disability known, and it is the most common single gene disorder associated with autism (Belmonte and Bourgeron 2006; Reddy 2005). It is caused by the lack or deficiency of the FMR1 protein, FMRP (Loesch et al. 2004b). The typical physical features of FXS include prominent ears, hyperextensible finger joints, flat feet, soft skin, and in adolescence and adulthood large testicles (macroorchidism) and a long face (Hagerman 2002b). The behavioral features include poor eye contact, hyperarousal to stimuli, anxiety, hyperactivity, attention deficit, impulsivity, hand stereotypies (such as hand biting and hand flapping), and social deficits including autism and autism spectrum disorder (ASD) (Budimirovic et al. 2006; Clifford et al. 2007; Hall et al. 2008b; Hatton et al. 2006b; Sullivan et al. 2007b). Fragile-X syndrome was first reported by Lubs (1969) in two brothers who had intellectual disability and the appearance of a marker X chromosome, which is a fragile site on their X chromosome. It was later detected that this fragile site on the X chromosome only occurred when the chromosomes were studied in a folate-deficient tissue culture media (Sutherland 1977). Therefore cytogenetic studies were utilized to document cases of FXS throughout the 1980s until the Fragile X Mental Retardation 1 gene (FMR1) was discovered in 1991 (Verkerk et al. 1991). The FMR1 gene was found to have a trinucleotide (CGG) repeat sequence at the 5’ untranslated region, with the normal range later determined to be up to 44 repeats, a gray zone of 45–54 repeats, a premutation of 55–200 repeats, and a full mutation range of more than 200 repeats (Maddalena et al. 2001). Those individuals with the full mutation have a deficit or absence of the FMR1 protein (FMRP) that causes the physical, behavioral, and cognitive features of FXS (Loesch et al. 2004b). Females with the full mutation have another X chromosome that is producing FMRP, depending on the activation ratio (AR) or the percentage of cells that have the normal X chromosome as the active X chromosome.

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Cascade Testing for Fragile X Syndrome in a Rural Setting in Cameroon (Sub-Saharan Africa)

Genes ◽

10.3390/genes11020136 ◽

2020 ◽

Vol 11 (2) ◽

pp. 136

Author(s):

Karen Kengne Kamga ◽

Séraphin Nguefack ◽

Khuthala Minka ◽

Edmond Wonkam Tingang ◽

Alina Esterhuizen ◽

...

Keyword(s):

Fragile X Syndrome ◽

Fragile X ◽

Autism Spectrum ◽

Sub Saharan Africa ◽

Rural Setting ◽

Premature Menopause ◽

Molecular Testing ◽

Full Mutation ◽

Cgg Repeat ◽

Cgg Repeats

Fragile X Syndrome (FXS), an X-linked dominant monogenic condition, is the main genetic cause of intellectual disability (ID) and autism spectrum disorder (ASD). FXS is associated with an expansion of CGG repeat sequence in the Fragile X Mental Retardation gene 1 (FMR1) on chromosome X. Following a neuropediatric assessment of two male siblings who presented with signs of FXS that was confirmed with molecular testing, we provided cascade counselling and testing to the extended family. A total of 46 individuals were tested for FXS; among them, 58.70% (n = 27) were females. The mean age was 9.4 (±5) years for children and 45.9 (±15.9) years for adults. Pedigree analysis suggested that the founder of these families was likely a normal transmitting male. Four out of 19 males with clinical ID were confirmed to have a full mutation for FXS, while 14/27 females had a pathologic CGG expansion (>56 CGG repeats) on one of their X chromosomes. Two women with premature menopause were confirmed of being carriers of premutation (91 and 101 CGG repeats). We also identified maternal alleles (91 and 126 CGG repeats) which expanded to a full mutation in their offspring (>200 CGG repeats). This study is a rare report on FXS from Africa and illustrates the case scenario of implementing genetic medicine for a neurogenetic condition in a rural setting.

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Urine-Derived Epithelial Cell Lines: A New Tool to Model Fragile X Syndrome (FXS)

Cells ◽

10.3390/cells9102240 ◽

2020 ◽

Vol 9 (10) ◽

pp. 2240

Author(s):

Marwa Zafarullah ◽

Mittal Jasoliya ◽

Flora Tassone

Keyword(s):

Epithelial Cell ◽

Epithelial Cells ◽

Fragile X Syndrome ◽

Cell Lines ◽

Behavioral Problems ◽

Cell Model ◽

Fragile X ◽

Healthy Controls ◽

Full Mutation ◽

Epithelial Cell Lines

Fragile X syndrome (FXS) is an X-linked neurodevelopmental condition associated with intellectual disability and behavioral problems due to the lack of the Fragile X mental retardation protein (FMRP), which plays a crucial role in synaptic plasticity and memory. A desirable in vitro cell model to study FXS would be one that can be generated by simple isolation and culture method from a collection of a non-invasive donor specimen. Currently, the various donor-specific cells can be isolated mainly from peripheral blood and skin biopsy. However, they are somewhat invasive methods for establishing cell lines from the primary subject material. In this study, we characterized a cost-effective and straightforward method to derive epithelial cell lines from urine samples collected from participants with FXS and healthy controls (TD). The urine-derived cells expressed epithelial cell surface markers via fluorescence-activated cell sorting (FACS). We observed inter, and the intra-tissue CGG mosaicism in the PBMCs and the urine-derived cells from participants with FXS potentially related to the observed variations in the phenotypic and clinical presentation FXS. We characterized these urine-derived epithelial cells for FMR1 mRNA and FMRP expression and observed some expression in the lines derived from full mutation mosaic participants. Further, FMRP expression was localized in the cytoplasm of the urine-derived epithelial cells of healthy controls. Deficient FMRP expression was also observed in mosaic males, while, as expected, no expression was observed in cells derived from participants with a hypermethylated full mutation.

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Incomplete silencing of full mutation alleles in males with fragile X syndrome is associated with autistic features

Molecular Autism ◽

10.1186/s13229-019-0271-7 ◽

2019 ◽

Vol 10 (1) ◽

Cited By ~ 7

Author(s):

Emma K. Baker ◽

Marta Arpone ◽

Solange M. Aliaga ◽

Lesley Bretherton ◽

Claudine M. Kraan ◽

...

Keyword(s):

Fragile X Syndrome ◽

Fragile X ◽

Full Mutation

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Qualitative assessment of FMR1 (CGG)n triplet repeat status in normal, intermediate, premutation, full mutation, and mosaic carriers in both sexes: Implications for fragile X syndrome carrier and newborn screening

Genetics in Medicine ◽

10.1097/gim.0b013e3181d0d40e ◽

2010 ◽

Vol 12 (3) ◽

pp. 162-173 ◽

Cited By ~ 55

Author(s):

Feras M Hantash ◽

Dana G Goos ◽

David Tsao ◽

Franklin Quan ◽

Arlene Buller-Burckle ◽

...

Keyword(s):

Newborn Screening ◽

Fragile X Syndrome ◽

Fragile X ◽

Qualitative Assessment ◽

Triplet Repeat ◽

Full Mutation

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Selection in blood cells from female carriers of the fragile X syndrome: inverse correlation between age and proportion of active X chromosomes carrying the full mutation.

Journal of Medical Genetics ◽

10.1136/jmg.28.12.830 ◽

1991 ◽

Vol 28 (12) ◽

pp. 830-836 ◽

Cited By ~ 71

Author(s):

F Rousseau ◽

D Heitz ◽

I Oberle ◽

J L Mandel

Keyword(s):

Fragile X Syndrome ◽

Blood Cells ◽

Fragile X ◽

Inverse Correlation ◽

Full Mutation ◽

X Chromosomes ◽

Female Carriers

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Targeted Reactivation of FMR1 Transcription in Fragile X Syndrome Embryonic Stem Cells

10.1101/286732 ◽

2018 ◽

Author(s):

Jill M. Haenfler ◽

Geena Skariah ◽

Caitlin M. Rodriguez ◽

Andre Monteiro da Rocha ◽

Jack M. Parent ◽

...

Keyword(s):

Mrna Expression ◽

Fragile X Syndrome ◽

Fragile X ◽

Embryonic Stem ◽

Transcriptional Silencing ◽

Hesc Line ◽

Human Patient ◽

Cgg Repeat ◽

Heterochromatin Formation ◽

Fmr1 Mrna

ABSTRACTFragile X Syndrome (FXS) is the most common inherited cause of intellectual disability and autism. It results from expansion of a CGG nucleotide repeat in the 5’ untranslated region of FMR1. Large expansions elicit repeat and promoter hyper-methylation, heterochromatin formation, FMR1 transcriptional silencing, and loss of the Fragile X protein, FMRP. Efforts aimed at correcting the sequelae resultant from FMRP loss have thus far proven insufficient, perhaps because of FMRP’s pleiotropic functions. As the repeats do not disrupt the FMRP coding sequence, reactivation of endogenous FMR1 gene expression could correct the proximal event in FXS pathogenesis. Here we utilize the CRISPR/dCAS9 system to selectively re-activate transcription from the silenced FMR1 locus. Fusion of the transcriptional activator VP192 to dCAS9 robustly enhances FMR1 transcription and increases FMRP levels when targeted directly to the CGG repeat in human cells. Using a previously uncharacterized FXS human embryonic stem cell (hESC) line which acquires transcriptional silencing with serial passaging, we achieved locus-specific transcriptional re-activation of FMR1 mRNA expression despite promoter and repeat methylation. These studies demonstrate that FMR1 mRNA expression can be selectively reactivated in human patient cells, creating a pathway forward for therapeutic development in Fragile X Syndrome.

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