scholarly journals Fragile X mental retardation 1 gene enhances the translation of large autism-related proteins

Science ◽  
2018 ◽  
Vol 361 (6403) ◽  
pp. 709-712 ◽  
Author(s):  
Ethan J. Greenblatt ◽  
Allan C. Spradling
Keyword(s):  
Mental Retardation ◽  
Messenger Rna ◽  
Fragile X ◽  
Mrna Translation ◽  
Autism Spectrum ◽  
Ribosome Profiling ◽  
Large Proteins ◽  
Fragile X Mental Retardation ◽  
Stored Mrna ◽  
Related Proteins

Mutations in the fragile X mental retardation 1 gene (FMR1) cause the most common inherited human autism spectrum disorder. FMR1 influences messenger RNA (mRNA) translation, but identifying functional targets has been difficult. We analyzed quiescent Drosophila oocytes, which, like neural synapses, depend heavily on translating stored mRNA. Ribosome profiling revealed that FMR1 enhances rather than represses the translation of mRNAs that overlap previously identified FMR1 targets, and acts preferentially on large proteins. Human homologs of at least 20 targets are associated with dominant intellectual disability, and 30 others with recessive neurodevelopmental dysfunction. Stored oocytes lacking FMR1 usually generate embryos with severe neural defects, unlike stored wild-type oocytes, which suggests that translation of multiple large proteins by stored mRNAs is defective in fragile X syndrome and possibly other autism spectrum disorders.

scholarly journals Fragile X mental retardation protein is a size-dependent translational activator

2018 ◽  
Author(s):  
Ethan J. Greenblatt ◽  
Allan C. Spradling
Keyword(s):  
Mental Retardation ◽  
Intellectual Disability ◽  
Fragile X ◽  
Ovarian Follicle ◽  
Autism Spectrum ◽  
Ribosome Profiling ◽  
Large Proteins ◽  
Fragile X Mental Retardation ◽  
Stored Mrna ◽  
Neural Dysfunction

SummaryFMR1 enhances translation of large neural/oocyte proteinsMutations in the highly conserved Fragile X mental retardation gene (Fmr1) cause the most common inherited human intellectual disability/autism spectrum disorder. Fmr1 is also needed for ovarian follicle development, and lesions are the largest genetic cause of premature ovarian failure (POF). FMR1 associates with ribosomes and is thought to repress translation, but identifying functional targets has been difficult. We analyzed FMR1’s role in quiescent Drosophila oocytes stored prior to ovulation, cells that depend entirely on translation of stored mRNA. Ribosome profiling revealed that in quiescent oocytes FMR1 stimulates the translation of large proteins, including at least twelve proteins whose human homologs are associated with dominant intellectual disability disorders, and 25 others associated with neural dysfunction. Knockdown of Fmr1 in unstored oocytes did not affect embryo development, but more than 50% of embryos derived from stored oocytes lacking FMR1 developed severe neural defects. Fmr1’s previously unappreciated role promoting the translation of large proteins from stored mRNAs in oocytes and neurons may underlie POF as well as multiple aspects of neural dysfunction.

scholarly journals ASFMR1splice variant

2018 ◽  
Vol 4 (4) ◽  
pp. e246 ◽  
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.

scholarly journals Structural Studies of the Tandem Tudor Domains of Fragile X Mental Retardation Related Proteins FXR1 and FXR2

PLoS ONE ◽  
2010 ◽  
Vol 5 (11) ◽  
pp. e13559 ◽  
Author(s):  
Melanie A. Adams-Cioaba ◽  
Yahong Guo ◽  
ChuanBing Bian ◽  
Maria F. Amaya ◽  
Robert Lam ◽  
...  
Keyword(s):  
Mental Retardation ◽  
Fragile X ◽  
Structural Studies ◽  
Fragile X Mental Retardation ◽  
Related Proteins

Focal areas of a high rate of fragile X in Indonesia: a long term follow up

2019 ◽  
Vol 5 (2) ◽  
pp. 67-68
Author(s):  
Sultana MH Faradz ◽  
Tri Indah Winarni
Keyword(s):  
Mental Retardation ◽  
Behavioral Problems ◽  
Fragile X ◽  
Autism Spectrum ◽  
High Rate ◽  
Learning Ability ◽  
Fragile X Mental Retardation ◽  
Cgg Repeats ◽  
Long Term Follow Up

Fragile X syndrome (FXS) is the most common cause of inherited intellectual disability (ID) and a leading cause of autism spectrum disorder (ASD). FXS is caused by an expansion of CGG repeats >200 in the 5′ untranslated region of the promotor region fragile X mental retardation 1 gene (FMR1), which is located on Xq27.3.  The abnormal CGG expansion leads to methylation and transcriptional silencing of the FMR1 gene, resulting in a reduction or loss of fragile X mental retardation 1 protein (FMRP) and causes long, thin, and immature dendritic spines, which lead to deficits in cognitive function, behavioral problems, and learning ability

scholarly journals Oligomerization properties of fragile-X mental-retardation protein (FMRP) and the fragile-X-related proteins FXR1P and FXR2P

1999 ◽  
Vol 343 (3) ◽  
pp. 517-523 ◽  
Author(s):  
Filippo TAMANINI ◽  
Leontine VAN UNEN ◽  
Cathy BAKKER ◽  
Nicoletta SACCHI ◽  
Hans GALJAARD ◽  
...  
Keyword(s):  
Mental Retardation ◽  
Mammalian Cells ◽  
Fragile X ◽  
Gel Filtration ◽  
Fragile X Mental Retardation ◽  
Mental Retardation Protein ◽  
Heterotypic Interactions ◽  
Molecular Masses ◽  
Related Proteins

The absence of fragile-X mental-retardation protein (FMRP) results in fragile-X syndrome. Two other fragile-X-related (FXR) proteins have been described, FXR1P and FXR2P, which are both very similar in amino acid sequence to FMRP. Interaction between the three proteins as well as with themselves has been demonstrated. The FXR proteins are believed to play a role in RNA metabolism. To characterize a possible functional role of the interacting proteins the complex formation of the FXR proteins was studied in mammalian cells. Double immunofluorescence analysis in COS cells over-expressing either FMRP ISO12/FXR1P or FMRP ISO12/FXR2P confirmed heterotypic interactions. However, Western-blotting studies on cellular homogenates containing physiological amounts of the three proteins gave different indications. Gel-filtration experiments under physiological as well as EDTA conditions showed that the FXR proteins were in complexes of > 600 kDa, as parts of messenger ribonuclear protein (mRNP) particles associated with polyribosomes. Salt treatment shifted FMRP, FXR1P and FXR2P into distinct intermediate complexes, with molecular masses between 200 and 300 kDa. Immunoprecipitations of FMRP as well as FXR1P from the dissociated complexes revealed that the vast majority of the FXR proteins do not form heteromeric complexes. Further analysis by [35S]methionine labelling in vivo followed by immunoprecipitation indicated that no proteins other than the FXR proteins were present in these complexes. These results suggest that the FXR proteins form homo-multimers preferentially under physiological conditions in mammalian cells, and might participate in mRNP particles with separate functions.

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