Human Disease Model Report: fragile X tremor/ataxia syndrome

General Information

Name

fragile X tremor/ataxia syndrome

FlyBase ID

FBhh0000137

Disease Ontology Term

fragile X-associated tremor/ataxia syndrome

Parent Disease

OMIM

FRAGILE X TREMOR/ATAXIA SYNDROME; FXTAS

Overview

Fragile X tremor/ataxia syndrome (FXTAS) is one of several syndromes caused by mutation in the FMR1 gene, which encodes a component of an RNA-binding complex that binds to the mRNA cap and mediates translational repression. The causative genetic lesion of fragile X tremor/ataxia syndrome is a trinucleotide (CGG)n repeat expansion within the 5' UTR of the FMR1 mRNA; (CGG)n repeat expansion in the range of 55-200 repeats is implicated in FXTAS. Since the phenotypic effects are less severe, expansions in this range are described as "premutation." See the human disease reports for fragile X syndromes (FBhh0000123) and fragile X mental retardation syndrome (FBhh0000136) for additional information about fragile X models in flies.

The mechanism causing FXTAS differs from that causing fragile X mental retardation syndrome. Silencing of the FMR1 gene is not observed; transcription continues to occur (often at higher level) and the FMR1 protein is functional. Symptoms are late-onset and of variable penetrance. It is postulated that repeat-associated non-AUG-initiated translation (RAN) from the FMR1 5'-leader produces toxic proteins that cause or contribute to the FXTAS neurodegeneration phenotypes.

In experiments in flies using (CGG)n-only constructs (curated under the synthetic gene Zzzz\CGG), transcribed premutation repeats alone are sufficient to cause neurodegeneration. This system has also been used in experiments assessing the role of RAN in FXTAS.

[updated Jul. 2021 by FlyBase; FBrf0222196]

Disease Summary Information

Disease Summary: fragile X tremor/ataxia syndrome

OMIM report

[FRAGILE X TREMOR/ATAXIA SYNDROME; FXTAS](https://omim.org/entry/300623)

Human gene(s) implicated

[FRAGILE X MESSENGER RIBONUCLEOPROTEIN 1; FMR1](https://omim.org/entry/309550)

Symptoms and phenotype

FXTAS is a late-onset progressive disorder characterized initially by progressive intention tremor and gait unsteadiness; cognitive decline may be observed later in the course of the disease. [from MIM:300623; 2016.01.15]

(OMIM, 2013-)

Genetics

The penetrance of FXTAS in male carriers aged 50 years and over, ascertained through families with a fragile X syndrome proband, is at least 33% (Hagerman and Hagerman, 2004; pubmed:15052536); its penetrance in female carriers is approximately 5-10% (Greco et al., 2008; pubmed:18695063). [from MIM:300623; 2016.01.15]

(OMIM, 2013-)

Cellular phenotype and pathology

Molecular information

Repeat-associated non-AUG-initiated translation of expanded CGG repeats (CGG RAN) from the FMR1 5'-leader is postulated to produce toxic proteins that contribute to neurodegeneration in fragile X-associated tremor/ataxia syndrome (Rodriguez et al., 2020; pubmed:32066985).

(FlyBase Curators, 2013-)

In the normal case, unexpanded CGG repeats and their translation appear to play roles in regulating fragile X protein (FMRP) synthesis. In neurons, CGG RAN acts as an inhibitory upstream open reading frame to suppress basal FMRP production (Rodriguez et al., 2020; pubmed:32066985).

(FlyBase Curators, 2013-)

The disease-implicated CGG-repeat tract is contained within the 5-prime untranslated region (5' UTR) of the FMR1 mRNA. In FXTAS, the levels of the FMR1 mRNA are higher than normal (Hagerman et al., 2001; pubmed:11445641). However, overexpression of the mRNA from the premutation expanded alleles is not associated with increased levels of FMR1 protein, suggesting that higher levels of the repeat-containing mRNA itself results in pathological effects (Primerano et al., 2002; pubmed:12515381). [from MIM:300624, MIM:300623, MIM:309550; 2016.01.15]

(OMIM, 2013-)

External links

Gene2Function (human gene): FMR1
Gene Cards: FMR1
GeneReviews, NCBI Bookshelf: FMR1-Related Disorders
MedlinePlus (condition): Fragile X-associated tremor/ataxia syndrome
MARRVEL (human gene): FMR1
NCBI MedGen: Fragile X tremor/ataxia syndrome (FXTAS)
NCBI (Entrez) gene: FMR1; fragile X messenger ribonucleoprotein 1

Disease synonyms

fragile X premutation

fragile X sydrome

FXTAS

Related Diseases

Related human health report(s)

fragile-X-related syndromes

fragile X syndrome

RNA repeat diseases

Ortholog Information

Human gene(s) in FlyBase

Other mammalian ortholog(s) used

D. melanogaster Gene Information (0)

Other Genes Used: Viral, Bacterial, Synthetic (1)

Zzzz\CGG

Summary of Physical Interactions (0 groups)

Alleles Reported to Model Human Disease (Disease Ontology) (4 alleles)

Zzzz\CGG

Models Based on Experimental Evidence ( 4 )

Allele

Disease

Evidence

References

Zzzz\CGG^{100.5'UTR.UAS.GFP}

model of fragile X-associated tremor/ataxia syndrome

CEA

(Oh et al., 2015)

Zzzz\CGG^90.UAS.EGFP

model of fragile X-associated tremor/ataxia syndrome

CEA

(Bhat et al., 2021, Malik et al., 2021, Kong et al., 2019, Linsalata et al., 2019, Weber et al., 2016, Oh et al., 2015, Galloway et al., 2014, Tan et al., 2012, Sofola et al., 2007, Sofola et al., 2007)

CEC

(Jin et al., 2007)

model of fragile X syndrome

CEA

(Zhang et al., 2018, Todd et al., 2013)

model of neurodegenerative disease

CEA

(Green et al., 2022, Peng et al., 2021, He et al., 2014, Todd et al., 2013, Qurashi et al., 2012, Tan et al., 2012, Todd et al., 2010, Jin et al., 2003)

model of primary ovarian insufficiency

CEA

(Trevino et al., 2021)

model of frontotemporal dementia and/or amyotrophic lateral sclerosis 1

CEA

(Glineburg et al., 2024)

Zzzz\CGG^60.UAS.EGFP

model of neurodegenerative disease

CEA

(Qurashi et al., 2012)

model of fragile X-associated tremor/ataxia syndrome

CEA

(Bhat et al., 2021, Tan et al., 2012)

Zzzz\CGG^103.UAS.EGFP

model of fragile X-associated tremor/ataxia syndrome

CEA

(Singh et al., 2021)

Modifiers Based on Experimental Evidence ( 4 )

Allele

Disease

Interaction

References

Zzzz\CGG^{100.5'UTR.UAS.GFP}

model of fragile X-associated tremor/ataxia syndrome

is exacerbated by Prosβ6^1.B.UAS

(Oh et al., 2015)

is exacerbated by Prosβ2^1.UAS

(Oh et al., 2015)

Zzzz\CGG^90.UAS.EGFP

ameliorates fragile X-associated tremor/ataxia syndrome

modeled by Zzzz\CCG^90.UAS.EGFP

(Sofola et al., 2007)

model of fragile X-associated tremor/ataxia syndrome

is ameliorated by Zzzz\CCG^90.UAS.EGFP

(Sofola et al., 2007)

is ameliorated by Hsap\TARDBP^UAS.cLa

(Galloway et al., 2014)

is exacerbated by TBPH^GD6943

(Galloway et al., 2014)

is ameliorated by Hsap\CELF1^UAS.cdHa

(Sofola et al., 2007)

is ameliorated by Hsap\HNRNPA2B1^UAS.cSa

(Sofola et al., 2007)

is ameliorated by Hrb87F^UAS.cSa

(Sofola et al., 2007)

is ameliorated by Hrb98DE^UAS.cSa

(Sofola et al., 2007)

is exacerbated by Prosβ6^1.B.UAS

(Oh et al., 2015)

is exacerbated by Prosβ2^1.UAS

(Oh et al., 2015)

is ameliorated by Hsc70-4^UAS.cEa

(Oh et al., 2015)

is ameliorated by Pur-α^UAS.Tag:FLAG

(Jin et al., 2007)

is ameliorated by bgcn^GD10012

(Linsalata et al., 2019)

is ameliorated by bgcn^KK106752

(Malik et al., 2021, Linsalata et al., 2019)

is ameliorated by eIF1^EY02210

(Linsalata et al., 2019)

is ameliorated by eIF1^GLC01849

(Linsalata et al., 2019)

is exacerbated by Rhau^EY09315

(Linsalata et al., 2019)

is exacerbated by RpS25^GD10582

(Linsalata et al., 2019)

is ameliorated by eIF1^HMC04556

(Linsalata et al., 2019)

is exacerbated by RpS25^KK107958

(Linsalata et al., 2019)

is exacerbated by eIF1^HMC04556

(Linsalata et al., 2019)

is ameliorated by SF2^HM05199

(Malik et al., 2021, Linsalata et al., 2019)

is exacerbated by eIF1^KK109232

(Linsalata et al., 2019)

is ameliorated by SF2^HMS00358

(Malik et al., 2021, Linsalata et al., 2019)

is exacerbated by eIF1A⁶⁴⁵

(Linsalata et al., 2019)

is ameliorated by bel⁵

(Linsalata et al., 2019)

is ameliorated by bel⁶

(Linsalata et al., 2019)

is exacerbated by eIF1A^GD10618

(Linsalata et al., 2019)

is ameliorated by bel^GD1324

(Linsalata et al., 2019)

is exacerbated by eIF1A^JF01698

(Linsalata et al., 2019)

is ameliorated by bel^GL00057

(Linsalata et al., 2019)

is ameliorated by bel^GL00205

(Linsalata et al., 2019)

is exacerbated by eIF1A^JF02475

(Linsalata et al., 2019)

is ameliorated by bel^JF02884

(Linsalata et al., 2019)

is ameliorated by bel^L4740

(Linsalata et al., 2019)

is exacerbated by eIF1A^KK108681

(Linsalata et al., 2019)

is ameliorated by bel^S074407

(Linsalata et al., 2019)

is exacerbated by eIF2α^815-29

(Linsalata et al., 2019)

is ameliorated by bel^cap-1

(Linsalata et al., 2019)

is exacerbated by eIF2α^GD1430

(Linsalata et al., 2019)

is exacerbated by eIF2α^KK100282

(Linsalata et al., 2019)

is exacerbated by eIF3b^EY14430

(Linsalata et al., 2019)

is ameliorated by eIF4B^GD7103

(Linsalata et al., 2019)

is exacerbated by eIF4B^GD7103

(Linsalata et al., 2019)

is ameliorated by eIF4H1^KK108805

(Linsalata et al., 2019)

is ameliorated by eIF4H2^KK103972

(Linsalata et al., 2019)

is ameliorated by CG4306^HMC06152

(Kong et al., 2019)

is exacerbated by CG8353^HMS03373

(Kong et al., 2019)

is exacerbated by ChAT^HMC05021

(Kong et al., 2019)

is exacerbated by Pect^HMJ30278

(Kong et al., 2019)

is exacerbated by Ppat-Dpck^HMC04615

(Kong et al., 2019)

is exacerbated by Sk2^HMS03001

(Kong et al., 2019)

is exacerbated by ras^JF01445

(Kong et al., 2019)

is exacerbated by schlank^JF02502

(Kong et al., 2019)

is ameliorated by Pur-α^UAS.cWa

(Weber et al., 2016)

is ameliorated by Pur-α^RI.RII.UAS

(Weber et al., 2016)

is exacerbated by lncRNA:flam^BG02658

(Tan et al., 2012)

is exacerbated by lncRNA:flam^KG00476

(Tan et al., 2012)

is ameliorated by bsk¹

(Bhat et al., 2021)

is ameliorated by Drep2^ex13

(Bhat et al., 2021)

is exacerbated by Cbp80^KK100796

(Malik et al., 2021)

is exacerbated by Hel25E^HMS00076

(Malik et al., 2021)

is exacerbated by Hel25E^k11511

(Malik et al., 2021)

is exacerbated by Pabp2^HMS00553

(Malik et al., 2021)

is ameliorated by RpLP0^JF01335

(Malik et al., 2021)

is ameliorated by SC35^EY07391

(Malik et al., 2021)

is ameliorated by SC35^HMC06150

(Malik et al., 2021)

is exacerbated by SF2^UAS.Tag:HA

(Malik et al., 2021)

is ameliorated by SRPK^HMS04491

(Malik et al., 2021)

is ameliorated by SRPK^HMS04507

(Malik et al., 2021)

is exacerbated by Syp^HMC04412

(Malik et al., 2021)

is exacerbated by Syp^MI11035

(Malik et al., 2021)

is ameliorated by eIF3g1^GLC01430

(Malik et al., 2021)

is exacerbated by glo^HMS00079

(Malik et al., 2021)

is ameliorated by B52^HMS01661

(Malik et al., 2021)

model of neurodegenerative disease

is ameliorated by Hsc70-4^UAS.cEa

(Jin et al., 2003)

is exacerbated by Hsc70-4^K71S.UAS

(Jin et al., 2003)

is ameliorated by GIIIspla2^EP1516

(Qurashi et al., 2012)

is ameliorated by GIIIspla2^GD17243

(Qurashi et al., 2012)

is ameliorated by HDAC3^{UAS.Tag:V5,Tag:polyHis}

(Todd et al., 2010)

is exacerbated by HDAC6^RNAi.UAS

(Todd et al., 2010)

is ameliorated by HDAC6^{UAS.Tag:V5,Tag:polyHis}

(Todd et al., 2010)

is ameliorated by HDAC11^{UAS.Tag:V5,Tag:polyHis}

(Todd et al., 2010)

is exacerbated by HDAC11^RNAi.UAS

(Todd et al., 2010)

is exacerbated by vimar^k16722

(Tan et al., 2012)

is exacerbated by Drep2^KG02396

(Tan et al., 2012)

is ameliorated by Avic\GFP^{EGFP.Scer\UAS.P\T.mir-276aSP}

(Tan et al., 2012)

is exacerbated by mir-277^UAS.cTa

(Tan et al., 2012)

is ameliorated by Drep2^d00223

(Tan et al., 2012)

is ameliorated by DENR^GD17852

(Green et al., 2022)

is ameliorated by DENR^KK109336

(Green et al., 2022)

is exacerbated by Hrb87F^JF01757

(He et al., 2014)

is exacerbated by Hsap\TARDBP^{M337V.UAS.Tag:MYC}

(He et al., 2014)

is exacerbated by Hrb98DE^JF01249

(He et al., 2014)

is exacerbated by Hsap\FUS^UAS.Tag:HA

(He et al., 2014)

is exacerbated by Hsap\TARDBP^{NLSmut.UAS.Tag:MYC}

(He et al., 2014)

is ameliorated by Hsap\HNRNPA2B1^UAS.Tag:MYC

(He et al., 2014)

is ameliorated by Hsap\TARDBP^UAS.Tag:MYC

(He et al., 2014)

is ameliorated by Hsap\TARDBP^{UAS.cHa.Tag:HA}

(He et al., 2014)

is exacerbated by Hsap\TARDBP^{Δ321-366.UAS.Tag:HA}

(He et al., 2014)

is ameliorated by Hsap\TARDBP^{FFLL.UAS.Tag:HA}

(He et al., 2014)

is exacerbated by Hsap\TARDBP^{G294A.UAs.Tag:MYC}

(He et al., 2014)

model of primary ovarian insufficiency

is ameliorated by Pdha1^HMC04032

(Trevino et al., 2021)

is ameliorated by Sumo^HMS01540

(Trevino et al., 2021)

is ameliorated by dbe^HMS04474

(Trevino et al., 2021)

Zzzz\CGG^60.UAS.EGFP

model of fragile X-associated tremor/ataxia syndrome

is ameliorated by Hrb87F^UAS.cSa

(Tan et al., 2012)

is exacerbated by lncRNA:flam^BG02658

(Tan et al., 2012)

is exacerbated by lncRNA:flam^KG00476

(Tan et al., 2012)

Zzzz\CGG^103.UAS.EGFP

model of fragile X-associated tremor/ataxia syndrome

is exacerbated by kra^JF02556

(Singh et al., 2021)

is ameliorated by kra^UAS.Tag:FLAG

(Singh et al., 2021)

is exacerbated by kra^j9B6

(Singh et al., 2021)

Alleles Representing Disease-Implicated Variants

Genetic Tools, Stocks and Reagents

Sources of Stocks

Contact lab of origin for a reagent not available from a public stock center.

Bloomington Stock Center Disease Page

Related mammalian, viral, bacterial, or synthetic transgenes

Allele

Transgene

Publicly Available Stocks

Zzzz\CGG^103.UAS.EGFP

Zzzz\CGG^{100.5'UTR.UAS.GFP}

P{UAS-CGG100-5'UTR-GFP}

Zzzz\CGG^{100.5'ATG.UAS.GFP}

P{UAS-CGG100-5'ATG-GFP}

Zzzz\CGG^{100.5'Stop.UAS.GFP}

P{UAS-CGG100-5'Stop-GFP}

Zzzz\CGG^{100.3'UTR.UAS.GFP}

P{UAS-GFP-CGG100-3'UTR}

Selected Drosophila transgenes

Allele

Transgene

Publicly Available Stocks

RNAi constructs available

Allele

Transgene

Publicly Available Stocks

Selected Drosophila classical alleles

Allele

Allele class

Mutagen

Publicly Available Stocks

References (50)

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