FMR1 — Mediated Wiki

{{Short description|Human protein and coding gene}} {{cs1 config|name-list-style=vanc|display-authors=6}} {{Infobox_gene}}

[[Image:Fmr1.jpeg|thumb|280px|Location of ''FMR1'' on the X chromosome. ]]

'''''FMR1''''' ('''Fragile X Messenger Ribonucleoprotein 1''') is a human gene<ref name="pmid1710175">{{cite journal | vauthors = Verkerk AJ, Pieretti M, Sutcliffe JS, Fu YH, Kuhl DP, Pizzuti A, Reiner O, Richards S, Victoria MF, Zhang FP | title = Identification of a gene (FMR-1) containing a CGG repeat coincident with a breakpoint cluster region exhibiting length variation in fragile X syndrome | journal = Cell | volume = 65 | issue = 5 | pages = 905–14 | date = May 1991 | pmid = 1710175 | doi = 10.1016/0092-8674(91)90397-H | s2cid = 21463845 }}</ref> that codes for a protein called ''fragile X messenger ribonucleoprotein'', or FMRP.<ref name="pmid8515814">{{cite journal | vauthors = Verheij C, Bakker CE, de Graaff E, Keulemans J, Willemsen R, Verkerk AJ, Galjaard H, Reuser AJ, Hoogeveen AT, Oostra BA | title = Characterization and localization of the FMR-1 gene product associated with fragile X syndrome | journal = Nature | volume = 363 | issue = 6431 | pages = 722–4 | date = June 1993 | pmid = 8515814 | doi = 10.1038/363722a0 | bibcode = 1993Natur.363..722V | url = http://repub.eur.nl/pub/56659 | hdl = 1765/56659 | s2cid = 4331494 | hdl-access = free }}</ref> This protein, most commonly found in the brain, is essential for normal cognitive development and female reproductive function. Mutations of this gene can lead to fragile X syndrome, intellectual disability, FXPOI (Fragile X-associated primary ovarian insufficiency), autism, FXTAS (Fragile X-associated tremor/ataxia syndrome), developmental delays and other cognitive deficits.<ref>[https://www.genecards.org/cgi-bin/carddisp.pl?gene=FMR1 "Fragile X Messenger Ribonucleoprotein 1"] The Human Gene Compendium</ref> The FMR1 premutation is associated with a wide spectrum of clinical phenotypes that affect more than two million people worldwide.<ref name="pmid27338822">{{cite journal |vauthors=Milà M, Rodriguez-Revenga L, Matilla-Dueñas A |title=FMR1 Premutation: Basic Mechanisms and Clinical Involvement |journal=Cerebellum |volume=15 |issue=5 |pages=543–5 |date=October 2016 |pmid=27338822 |doi=10.1007/s12311-016-0808-7 |s2cid=16002209 }}</ref>

== Function ==

=== Synaptic plasticity ===

FMRP has a diverse array of functions throughout different areas of the neuron; however these functions have not been fully characterized. FMRP has been suggested to play roles in nucleocytoplasmic shuttling of mRNA, dendritic mRNA localization, and synaptic protein synthesis.<ref name="Antar2005">{{cite journal | vauthors = Antar LN, Dictenberg JB, Plociniak M, Afroz R, Bassell GJ | title = Localization of FMRP-associated mRNA granules and requirement of microtubules for activity-dependent trafficking in hippocampal neurons | journal = Genes, Brain and Behavior | volume = 4 | issue = 6 | pages = 350–9 | date = August 2005 | pmid = 16098134 | doi = 10.1111/j.1601-183X.2005.00128.x | doi-access = free }}</ref> Studies of Fragile X syndrome have significantly aided in the understanding of the functionality of FMRP through the observed effects of FMRP loss on neurons. A mouse model of Fragile X Messenger Ribonucleoprotein implicated the involvement of FMRP in synaptic plasticity.<ref>{{cite journal | vauthors = Huber KM, Gallagher SM, Warren ST, Bear MF | title = Altered synaptic plasticity in a mouse model of fragile X mental retardation | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 99 | issue = 11 | pages = 7746–50 | date = May 2002 | pmid = 12032354 | pmc = 124340 | doi = 10.1073/pnas.122205699 | bibcode = 2002PNAS...99.7746H | doi-access = free }}</ref> Synaptic plasticity requires the production of new proteins in response to activation of synaptic receptors. It is the production of proteins in response to stimulation which is hypothesized to allow for the permanent physical changes and altered synaptic connections that are linked with the processes of learning and memory.

Group 1 metabotropic glutamate receptor (mGluR) signaling has been implicated in playing an important role in FMRP-dependent synaptic plasticity. Post-synaptic mGluR stimulation results in the up-regulation of protein synthesis through a second messenger system.<ref name=":0">{{cite journal | vauthors = Weiler IJ, Greenough WT | title = Metabotropic glutamate receptors trigger postsynaptic protein synthesis | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 90 | issue = 15 | pages = 7168–71 | date = August 1993 | pmid = 8102206 | pmc = 47097 | doi = 10.1073/pnas.90.15.7168 | bibcode = 1993PNAS...90.7168W | doi-access = free }}</ref> A role for mGluR in synaptic plasticity is further evidenced by the observation of dendritic spine elongation following mGluR stimulation.<ref>{{cite journal | vauthors = Vanderklish PW, Edelman GM | title = Dendritic spines elongate after stimulation of group 1 metabotropic glutamate receptors in cultured hippocampal neurons | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 99 | issue = 3 | pages = 1639–44 | date = February 2002 | pmid = 11818568 | pmc = 122243 | doi = 10.1073/pnas.032681099 | bibcode = 2002PNAS...99.1639V | doi-access = free }}</ref> Furthermore, mGluR activation results in the synthesis of FMRP near synapses. The produced FMRP associates with polyribosomal complexes after mGluR stimulation, proposing the involvement of Fragile X Messenger Ribonucleoprotein in the process of translation. This further advocates a role for FMRP in synaptic protein synthesis and the growth of synaptic connections.<ref name="Weiler1997">{{cite journal | vauthors = Weiler IJ, Irwin SA, Klintsova AY, Spencer CM, Brazelton AD, Miyashiro K, Comery TA, Patel B, Eberwine J, Greenough WT | title = Fragile X mental retardation protein is translated near synapses in response to neurotransmitter activation | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 94 | issue = 10 | pages = 5395–400 | date = May 1997 | pmid = 9144248 | pmc = 24689 | doi = 10.1073/pnas.94.10.5395 | bibcode = 1997PNAS...94.5395W | doi-access = free }}</ref> The loss of FMRP results in an abnormal dendritic spine phenotype. Specifically, deletion of the FMR1 gene in a sample of mice resulted in an increase in spine synapse number.<ref>{{cite journal | vauthors = Antar LN, Li C, Zhang H, Carroll RC, Bassell GJ | title = Local functions for FMRP in axon growth cone motility and activity-dependent regulation of filopodia and spine synapses | journal = Molecular and Cellular Neurosciences | volume = 32 | issue = 1–2 | pages = 37–48 | year = 2006 | pmid = 16631377 | doi = 10.1016/j.mcn.2006.02.001 | s2cid = 18257268 }}</ref>

=== Role in translation ===

The proposed mechanism of FMRP's effect upon synaptic plasticity are through its role as a negative regulator of translation. FMRP is an RNA-binding protein which associates with polyribosomes.<ref name="Weiler1997" /><ref>{{cite journal | vauthors = Brown V, Small K, Lakkis L, Feng Y, Gunter C, Wilkinson KD, Warren ST | title = Purified recombinant Fmrp exhibits selective RNA binding as an intrinsic property of the fragile X mental retardation protein | journal = The Journal of Biological Chemistry | volume = 273 | issue = 25 | pages = 15521–7 | date = June 1998 | pmid = 9624140 | doi = 10.1074/jbc.273.25.15521 | doi-access = free }}</ref> The RNA-binding abilities of FMRP are dependent upon its KH domains and RGG boxes. The KH domain is a conserved motif which characterizes many RNA-binding proteins. Mutagenesis of this domain resulted in impaired FMRP binding to RNA.<ref>{{cite journal | vauthors = Siomi H, Choi M, Siomi MC, Nussbaum RL, Dreyfuss G | title = Essential role for KH domains in RNA binding: impaired RNA binding by a mutation in the KH domain of FMR1 that causes fragile X syndrome | journal = Cell | volume = 77 | issue = 1 | pages = 33–9 | date = April 1994 | pmid = 8156595 | doi = 10.1016/0092-8674(94)90232-1 | s2cid = 35339859 }}</ref>

FMRP has been shown to inhibit translation of mRNA. Mutation of the FMRP protein resulted in the inability to repress translation as opposed to the wild-type counterpart which was able to do so in model systems (reticulocyte lysates and Xenopus laevis oocytes).<ref>{{cite journal | vauthors = Laggerbauer B, Ostareck D, Keidel EM, Ostareck-Lederer A, Fischer U | title = Evidence that fragile X mental retardation protein is a negative regulator of translation | journal = Human Molecular Genetics | volume = 10 | issue = 4 | pages = 329–38 | date = February 2001 | pmid = 11157796 | doi = 10.1093/hmg/10.4.329 | doi-access = free }}</ref> These observations were extended to the mouse brain, where crosslinking immunoprecipitation (CLIP) studies showed that FMRP binds to mRNA targets to stall ribosomes and inhibit translation, and does so in a reversible manner.<ref>{{cite journal | vauthors = Darnell JC, Van Driesche SJ, Zhang C, Hung KY, Mele A, Fraser CE, Stone EF, Chen C, Fak JJ, Chi SW, Licatalosi DD, Richter JD, Darnell RB | title = FMRP stalls ribosomal translocation on mRNAs linked to synaptic function and autism | journal = Cell | volume = 146 | issue = 2 | pages = 247–261 | date = July 2011 | pmid = 21784246 | pmc = 3232425 | doi = 10.1016/j.cell.2011.06.013 }}</ref> In purified synaptoneurosomes, mGluR stimulation results in increased levels of FMRP target mRNAs.<ref name=":0" /> A study found basal levels of proteins encoded by these target mRNAs to be significantly elevated and improperly regulated in FMRP deficient mice.<ref name="Hou2006">{{cite journal | vauthors = Hou L, Antion MD, Hu D, Spencer CM, Paylor R, Klann E | title = Dynamic translational and proteasomal regulation of fragile X mental retardation protein controls mGluR-dependent long-term depression | journal = Neuron | volume = 51 | issue = 4 | pages = 441–54 | date = August 2006 | pmid = 16908410 | doi = 10.1016/j.neuron.2006.07.005 | s2cid = 13915959 | doi-access = free }}</ref>

FMRP translation repression can act by inhibiting the initiation of translation. FMRP directly binds CYFIP1, which in turn binds the translation initiation factor eIF4E. The FMRP-CYFIP1 complex prohibits eIF4E-dependent initiation, thereby acting to repress translation.<ref name="Napoli2008">{{cite journal | vauthors = Napoli I, Mercaldo V, Boyl PP, Eleuteri B, Zalfa F, De Rubeis S, Di Marino D, Mohr E, Massimi M, Falconi M, Witke W, Costa-Mattioli M, Sonenberg N, Achsel T, Bagni C | title = The fragile X syndrome protein represses activity-dependent translation through CYFIP1, a new 4E-BP | journal = Cell | volume = 134 | issue = 6 | pages = 1042–54 | date = September 2008 | pmid = 18805096 | doi = 10.1016/j.cell.2008.07.031 | s2cid = 14123165 | doi-access = free }}</ref> When applied to the observed phenotype in fragile X Syndrome, the excess protein levels and reduction of translational control can be explained by the loss of translational repression by FMRP in fragile X syndrome.<ref name="Napoli2008" /><ref>{{cite journal | vauthors = Muddashetty RS, Kelić S, Gross C, Xu M, Bassell GJ | title = Dysregulated metabotropic glutamate receptor-dependent translation of AMPA receptor and postsynaptic density-95 mRNAs at synapses in a mouse model of fragile X syndrome | journal = The Journal of Neuroscience | volume = 27 | issue = 20 | pages = 5338–48 | date = May 2007 | pmid = 17507556 | doi = 10.1523/JNEUROSCI.0937-07.2007 | pmc = 6672337 | doi-access = free }}</ref> FMRP acts to control translation of a large group of target mRNAs; however the extent of FMRPs translational control is unknown. The protein has been shown to repress the translation of target mRNAs at synapses, including those encoding the cytoskeletal proteins Arc/Arg3.1 and MAP1B, and the CaM kinase II.<ref>{{cite journal | vauthors = Zalfa F, Giorgi M, Primerano B, Moro A, Di Penta A, Reis S, Oostra B, Bagni C | title = The fragile X syndrome protein FMRP associates with BC1 RNA and regulates the translation of specific mRNAs at synapses | journal = Cell | volume = 112 | issue = 3 | pages = 317–27 | date = February 2003 | pmid = 12581522 | doi = 10.1016/S0092-8674(03)00079-5 | s2cid = 14892764 | doi-access = free }}</ref> In addition, FMRP binds PSD-95 and GluR1/2 mRNAs. Importantly, these FMRP-binding mRNAs play significant roles in neuronal plasticity.

FMRP translational control has been shown to be regulated by mGluR signaling. mGluR stimulation may result in the transportation of mRNA complexes to synapses for local protein synthesis. FMRP granules have been shown to localize with MAP1B mRNA and ribosomal RNA in dendrites, suggesting this complex as a whole may need to be transported to dendrites for local protein synthesis. In addition, microtubules were found to be a necessary component for the mGluR-dependent translocation of FMRP into dendrites.<ref name="Antar2005" /> FMRP may play an additional role in local protein synthesis by aiding in the association of mRNA cargo and microtubules.<ref>{{cite journal | vauthors = Estes PS, O'Shea M, Clasen S, Zarnescu DC | title = Fragile X protein controls the efficacy of mRNA transport in Drosophila neurons | journal = Molecular and Cellular Neurosciences | volume = 39 | issue = 2 | pages = 170–9 | date = October 2008 | pmid = 18655836 | doi = 10.1016/j.mcn.2008.06.012 | s2cid = 24629325 }}</ref> Thus, FMRP is able to regulate transport efficacy, as well as repression of translation during transport. Finally, FMRP synthesis, ubiquitination, and proteolysis occur rapidly in response to mGluR signaling, suggesting an extremely dynamic role of the translational regulator.<ref name="Hou2006" />

== Gene expression ==

The ''FMR1'' gene is located on the X chromosome and contains a repeated CGG trinucleotide. In most people, the CGG segment is repeated approximately 5-44 times. Higher numbers of repeats of the CGG segment are associated with impaired cognitive and reproductive function. If a person has 45-54 repeats this is considered the "gray zone" or borderline risk, 55-200 repeats is called premutation, and more than 200 repeats is considered a full mutation of the FMR1 gene according to the American College of Medical Genetics and Genomics.<ref>{{cite web|url=http://www.acmg.net/Pages/ACMG_Activities/stds-2002/fx.htm |title=Technical Standards and Guidelines for Fragile X |publisher=American College of Medical Genetics |date=2000-10-02 |access-date=2013-03-29}}</ref> The first complete DNA sequence of the repeat expansion in someone with the full mutation was generated by scientists in 2012 using SMRT sequencing.<ref>{{cite journal | vauthors = Loomis EW, Eid JS, Peluso P, Yin J, Hickey L, Rank D, McCalmon S, Hagerman RJ, Tassone F, Hagerman PJ | title = Sequencing the unsequenceable: expanded CGG-repeat alleles of the fragile X gene | journal = Genome Research | volume = 23 | issue = 1 | pages = 121–8 | date = January 2013 | pmid = 23064752 | pmc = 3530672 | doi = 10.1101/gr.141705.112 }}</ref> This is an example of a trinucleotide repeat disorder. Trinucleotide repeat expansion is likely a consequence of strand slippage either during DNA repair or DNA replication.<ref name="pmid25608779">{{cite journal |vauthors=Usdin K, House NC, Freudenreich CH |title=Repeat instability during DNA repair: Insights from model systems |journal=Crit. Rev. Biochem. Mol. Biol. |volume=50 |issue=2 |pages=142–67 |date=2015 |pmid=25608779 |pmc=4454471 |doi=10.3109/10409238.2014.999192 }}</ref>

FMRP is a chromatin-binding protein that functions in the DNA damage response.<ref name="pmid24813610">{{cite journal |vauthors=Alpatov R, Lesch BJ, Nakamoto-Kinoshita M, Blanco A, Chen S, Stützer A, Armache KJ, Simon MD, Xu C, Ali M, Murn J, Prisic S, Kutateladze TG, Vakoc CR, Min J, Kingston RE, Fischle W, Warren ST, Page DC, Shi Y |title=A chromatin-dependent role of the fragile X mental retardation protein FMRP in the DNA damage response |journal=Cell |volume=157 |issue=4 |pages=869–81 |date=May 2014 |pmid=24813610 |pmc=4038154 |doi=10.1016/j.cell.2014.03.040 }}</ref><ref name="pmid29796988">{{cite journal |vauthors=Dockendorff TC, Labrador M |title=The Fragile X Protein and Genome Function |journal=Mol. Neurobiol. |volume= 56|issue= 1|pages= 711–721|date=May 2018 |pmid=29796988 |doi=10.1007/s12035-018-1122-9 |s2cid=44159474 }}</ref> FMRP occupies sites on meiotic chromosomes and regulates the dynamics of the DNA damage response machinery during spermatogenesis.<ref name="pmid24813610" />

The ''FMR1'' gene can be found on the long (q) arm of the X chromosome at position 27.3, from base pair 146,699,054 to base pair 146,738,156

== Related conditions ==

=== Fragile X syndrome ===

Almost all cases of fragile X syndrome are caused by expansion of the CGG trinucleotide repeat in the ''FMR1'' gene. In these cases, CGG is abnormally repeated from 200 to more than 1,000 times. As a result, this part of the ''FMR1'' gene is methylated, which silences the gene (it is turned off and does not make any protein). Without adequate FMR1, severe learning disabilities or intellectual disabilities can develop, along with physical abnormalities seen in fragile X syndrome.

Fewer than 1% of all cases of fragile X syndrome are caused by mutations that delete part or all of the ''FMR1'' gene, or change a base pair, leading to a change in one of the amino acids in the gene. These mutations disrupt the 3-dimensional shape of FMRP or prevent the protein from being synthesized, leading to the signs and symptoms of fragile X syndrome.

A CGG sequence in the ''FMR1'' gene that is repeated between 55 and 200 times is described as a premutation. Although most individuals with the premutation are intellectually normal, some of these individuals have mild versions of the physical features seen in fragile X syndrome (such as prominent ears) and may experience mental health problems such as anxiety or depression.

=== Fragile X-associated tremor/ataxia syndrome ===

Premutations are associated with an increased risk of fragile X-associated tremor/ataxia syndrome (FXTAS). FXTAS is characterized by ataxia (loss of coordination), tremor, memory loss, loss of sensation in the lower extremities (peripheral neuropathy) and mental and behavioral changes. The disorder usually develops late in life.

=== Premature ovarian aging ===

The FMR1 gene plays a very important role in ovarian function, independent from cognitive/neurological effects. Minor expansions of CGG repeats that do not cause fragile X syndrome are associated with an increased risk for premature ovarian aging, also called occult primary ovarian insufficiency, a condition in which women prematurely deplete their ovarian function.<ref name="pmid20955631">{{cite journal|author-link1=Norbert Gleicher| vauthors = Gleicher N, Barad DH | title = The FMR1 gene as regulator of ovarian recruitment and ovarian reserve | journal = Obstetrical & Gynecological Survey | volume = 65 | issue = 8 | pages = 523–30 | date = August 2010 | pmid = 20955631 | doi = 10.1097/OGX.0b013e3181f8bdda | s2cid = 26409068 }}</ref><ref name="pmid19712568">{{cite journal | vauthors = Chatterjee S, Maitra A, Kadam S, Patel Z, Gokral J, Meherji P | title = CGG repeat sizing in the FMR1 gene in Indian women with premature ovarian failure | journal = Reproductive Biomedicine Online | volume = 19 | issue = 2 | pages = 281–6 | date = August 2009 | pmid = 19712568 | doi = 10.1016/s1472-6483(10)60086-7 | doi-access = free }}</ref><ref name="pmid18973899">{{cite journal | vauthors = Streuli I, Fraisse T, Ibecheole V, Moix I, Morris MA, de Ziegler D | title = Intermediate and premutation FMR1 alleles in women with occult primary ovarian insufficiency | journal = Fertility and Sterility | volume = 92 | issue = 2 | pages = 464–70 | date = August 2009 | pmid = 18973899 | doi = 10.1016/j.fertnstert.2008.07.007 | doi-access = free }}</ref>

=== Polycystic ovarian syndrome ===

A very specific sub-genotype of FMR1 has been found to be associated with polycystic ovarian syndrome (PCOS). The gene expression, called heterozygous-normal/low may cause PCOS-like excessive follicle activity and hyperactive ovarian function when women are younger.

== Interactions ==

''FMR1'' has been shown to interact with: * CYFIP1,<ref name = pmid11438699>{{cite journal | vauthors = Schenck A, Bardoni B, Moro A, Bagni C, Mandel JL | title = A highly conserved protein family interacting with the fragile X mental retardation protein (FMRP) and displaying selective interactions with FMRP-related proteins FXR1P and FXR2P | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 98 | issue = 15 | pages = 8844–9 | date = July 2001 | pmid = 11438699 | pmc = 37523 | doi = 10.1073/pnas.151231598 | bibcode = 2001PNAS...98.8844S | doi-access = free }}</ref> * CYFIP2,<ref name = pmid11438699/><ref name = pmid12837692>{{cite journal | vauthors = Bardoni B, Castets M, Huot ME, Schenck A, Adinolfi S, Corbin F, Pastore A, Khandjian EW, Mandel JL | title = 82-FIP, a novel FMRP (fragile X mental retardation protein) interacting protein, shows a cell cycle-dependent intracellular localization | journal = Human Molecular Genetics | volume = 12 | issue = 14 | pages = 1689–98 | date = July 2003 | pmid = 12837692 | doi = 10.1093/hmg/ddg181 | doi-access = free }}</ref> * FXR1,<ref name = pmid8668200/><ref name = pmid7489725/> and * FXR2,<ref name = pmid8668200>{{cite journal | vauthors = Siomi MC, Zhang Y, Siomi H, Dreyfuss G | title = Specific sequences in the fragile X syndrome protein FMR1 and the FXR proteins mediate their binding to 60S ribosomal subunits and the interactions among them | journal = Molecular and Cellular Biology | volume = 16 | issue = 7 | pages = 3825–32 | date = July 1996 | pmid = 8668200 | pmc = 231379 | doi = 10.1128/mcb.16.7.3825 }}</ref><ref name = pmid7489725>{{cite journal | vauthors = Zhang Y, O'Connor JP, Siomi MC, Srinivasan S, Dutra A, Nussbaum RL, Dreyfuss G | title = The fragile X mental retardation syndrome protein interacts with novel homologs FXR1 and FXR2 | journal = The EMBO Journal | volume = 14 | issue = 21 | pages = 5358–66 | date = November 1995 | pmid = 7489725 | pmc = 394645 | doi = 10.1002/j.1460-2075.1995.tb00220.x}}</ref><ref name = pmid10567518>{{cite journal | vauthors = Ceman S, Brown V, Warren ST | title = Isolation of an FMRP-associated messenger ribonucleoprotein particle and identification of nucleolin and the fragile X-related proteins as components of the complex | journal = Molecular and Cellular Biology | volume = 19 | issue = 12 | pages = 7925–32 | date = December 1999 | pmid = 10567518 | pmc = 84877 | doi = 10.1128/mcb.19.12.7925 }}</ref> * NUFIP1,<ref name = pmid12837692/><ref name = pmid10556305>{{cite journal | vauthors = Bardoni B, Schenck A, Mandel JL | title = A novel RNA-binding nuclear protein that interacts with the fragile X mental retardation (FMR1) protein | journal = Human Molecular Genetics | volume = 8 | issue = 13 | pages = 2557–66 | date = December 1999 | pmid = 10556305 | doi = 10.1093/hmg/8.13.2557 | doi-access = free }}</ref> and * NUFIP2.<ref name = pmid12837692/>

== References == {{Reflist|35em}}

== Further reading == {{refbegin|35em}} * {{cite journal | vauthors = Bassell GJ, Warren ST | title = Fragile X syndrome: loss of local mRNA regulation alters synaptic development and function | journal = Neuron | volume = 60 | issue = 2 | pages = 201–14 | date = October 2008 | pmid = 18957214 | pmc = 3691995 | doi = 10.1016/j.neuron.2008.10.004 }} * {{cite journal | vauthors = Hagerman PJ, Hagerman RJ | title = The fragile-X premutation: a maturing perspective | journal = American Journal of Human Genetics | volume = 74 | issue = 5 | pages = 805–16 | date = May 2004 | pmid = 15052536 | pmc = 1181976 | doi = 10.1086/386296 }} * {{cite journal | vauthors = Hagerman RJ, Leavitt BR, Farzin F, Jacquemont S, Greco CM, Brunberg JA, Tassone F, Hessl D, Harris SW, Zhang L, Jardini T, Gane LW, Ferranti J, Ruiz L, Leehey MA, Grigsby J, Hagerman PJ | title = Fragile-X-associated tremor/ataxia syndrome (FXTAS) in females with the FMR1 premutation | journal = American Journal of Human Genetics | volume = 74 | issue = 5 | pages = 1051–6 | date = May 2004 | pmid = 15065016 | pmc = 1181968 | doi = 10.1086/420700 }} * {{cite journal | vauthors = Jacquemont S, Hagerman RJ, Leehey MA, Hall DA, Levine RA, Brunberg JA, Zhang L, Jardini T, Gane LW, Harris SW, Herman K, Grigsby J, Greco CM, Berry-Kravis E, Tassone F, Hagerman PJ | title = Penetrance of the fragile X-associated tremor/ataxia syndrome in a premutation carrier population | journal = JAMA | volume = 291 | issue = 4 | pages = 460–9 | date = January 2004 | pmid = 14747503 | doi = 10.1001/jama.291.4.460 | doi-access = free }} * {{cite journal | vauthors = Jin P, Alisch RS, Warren ST | title = RNA and microRNAs in fragile X mental retardation | journal = Nature Cell Biology | volume = 6 | issue = 11 | pages = 1048–53 | date = November 2004 | pmid = 15516998 | doi = 10.1038/ncb1104-1048 | s2cid = 7315938 }} * {{cite journal | vauthors = Jin P, Warren ST | title = New insights into fragile X syndrome: from molecules to neurobehaviors | journal = Trends in Biochemical Sciences | volume = 28 | issue = 3 | pages = 152–8 | date = March 2003 | pmid = 12633995 | doi = 10.1016/S0968-0004(03)00033-1 | citeseerx = 10.1.1.532.4162 }} * {{cite journal | vauthors = O'Donnell WT, Warren ST | title = A decade of molecular studies of fragile X syndrome | journal = Annual Review of Neuroscience | volume = 25 | pages = 315–38 | year = 2002 | pmid = 12052912 | doi = 10.1146/annurev.neuro.25.112701.142909 }} * {{cite journal | vauthors = Oostra BA, Chiurazzi P | title = The fragile X gene and its function | journal = Clinical Genetics | volume = 60 | issue = 6 | pages = 399–408 | date = December 2001 | pmid = 11846731 | doi = 10.1034/j.1399-0004.2001.600601.x | s2cid = 40128119 }} * {{cite journal | vauthors = Oostra BA, Willemsen R | title = A fragile balance: FMR1 expression levels | journal = Human Molecular Genetics | volume = 12 Spec No 2 | issue = 90002 | pages = R249–57 | date = October 2003 | pmid = 12952862 | doi = 10.1093/hmg/ddg298 | doi-access = free }} * {{cite journal | vauthors = Nicola NA, Metcalf D | title = Subunit promiscuity among hemopoietic growth factor receptors | journal = Cell | volume = 67 | issue = 1 | pages = 1–4 | date = October 1991 | pmid = 1913811 | doi = 10.1016/0092-8674(91)90564-F | s2cid = 12696714 }} * {{cite journal | vauthors = Sielska D, Milewski M, Bal J | title = [Molecular pathogenesis of fragile X syndrome] | journal = Medycyna Wieku Rozwojowego | volume = 6 | issue = 4 | pages = 295–308 | year = 2003 | pmid = 12810982 }} * {{cite journal | vauthors = Bagni C, Greenough WT | title = From mRNP trafficking to spine dysmorphogenesis: the roots of fragile X syndrome | journal = Nature Reviews. Neuroscience | volume = 6 | issue = 5 | pages = 376–87 | date = May 2005 | pmid = 15861180 | doi = 10.1038/nrn1667 | s2cid = 17374547 | url = https://lirias.kuleuven.be/handle/123456789/252990 | url-access = subscription }} * {{cite journal | vauthors = Huber KM | title = The fragile X-cerebellum connection | journal = Trends in Neurosciences | volume = 29 | issue = 4 | pages = 183–5 | date = April 2006 | pmid = 16500716 | doi = 10.1016/j.tins.2006.02.001 | s2cid = 8674692 }} * {{cite journal | vauthors = Loesch DZ, Bui QM, Dissanayake C, Clifford S, Gould E, Bulhak-Paterson D, Tassone F, Taylor AK, Hessl D, Hagerman R, Huggins RM | title = Molecular and cognitive predictors of the continuum of autistic behaviours in fragile X | journal = Neuroscience and Biobehavioral Reviews | volume = 31 | issue = 3 | pages = 315–26 | year = 2007 | pmid = 17097142 | pmc = 2145511 | doi = 10.1016/j.neubiorev.2006.09.007 }} {{refend}}

== External links == * [https://www.genecards.org/cgi-bin/carddisp?FMR1 GeneCard] * {{GeneTests|fragilex}}

Category:Genes mutated in mice Category:Genes on human chromosome X