Fragile X Syndrome
|Embryology - 3 Jul 2020 Expand to Translate|
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|A personal message from Dr Mark Hill (May 2020)|
|contributors to the site. The good news is Embryology will remain online and I will continue my association with UNSW Australia. I look forward to updating and including the many exciting new discoveries in Embryology!|
- 1 Introduction
- 2 Some Recent Findings
- 3 International Classification of Diseases
- 4 Fragile X-associated Tremor
- 5 Screening
- 6 FMRP and Cajal bodies
- 7 Mouse Model
- 8 References
- 9 External Links
- 10 Glossary Links
Fragile X Syndrome (Mental Retardation, X-linked, associated with marXq28, X-linked mental retardation and macroorchidism, Marker X syndrome, Martin-Bell syndrome).
Fragile X Syndrome (FXS) is the most common form of inherited mental retardation and autism. The condition is caused by a loss of the functional fragile X mental retardation protein (FMRP) an RNA-binding protein that can regulate the translation of specific mRNAs. There are several suggested additional roles for this protein including synaptic development and function and in adult neurogenesis.
The normal FMR1 functional gene can contain a trinucleotide sequence (CGG) repeated between 6 to 44 times. Expansion of this sequence (55 to 200 repeats) in an unmethylated form that generates an unstable sequence. This leads to repression of FMR1 transcription and subsequent decreased protein levels in the brain.
- 2014 - Fragile X Association of Australia Fund raiser Manly Wharf Bridge to Beach Paddle race
- 2011 - Undergraduate Science students project Fragile X Syndrome.
- Links: Neural Abnormalities | Neural System Development | 2011 Student Project - Fragile X Syndrome | Fragile X Association of Australia
Some Recent Findings
|More recent papers|
This table allows an automated computer search of the external PubMed database using the listed "Search term" text link.
Search term: Fragile X Syndrome
|These papers originally appeared in the Some Recent Findings table, but as that list grew in length have now been shuffled down to this collapsible table.
International Classification of Diseases
The International Classification of Diseases (ICD) World Health Organization's classification used worldwide as the standard diagnostic tool for epidemiology, health management and clinical purposes. This includes the analysis of the general health situation of population groups. It is used to monitor the incidence and prevalence of diseases and other health problems. Within this classification "congenital malformations, deformations and chromosomal abnormalities" are (Q00-Q99) but excludes "inborn errors of metabolism" (E70-E90).
Q99 Other chromosome abnormalities, not elsewhere classified
- Q99.2 Fragile X chromosome Fragile X syndrome
Fragile X-associated Tremor
(Ataxia Syndrome) A mainly male adult-onset condition that causes tremor and affects balance and memory in some "carriers" of the Fragile X gene. Because of the adult onset, this can be mistaken for a range of other neurological disorders including Parkinson's and Alzheimer's disease.
Screening By Country
- USA - Practice Guidelines of the National Society of Genetic Counselors - original version (2000), updated (2005), latest version (2012).
FMRP and Cajal bodies
A recent study has identified specific isoforms of the Fragile X protein (ISO6 and ISO12) are localised to the nuclear Cajal bodies. The authors have postulated a model (shown below) for these specific function in neurons.
|FMRP Localization in Neurons Model
Alternative splicing of the primary FMRP transcripts generates either ISO6 FMRP lacking the CRD domain, or ISO1 FMRP containing both NLS and CRD domains.
A Mouse Model of the Human Fragile X Syndrome I304N Mutation
- "The mental retardation, autistic features, and behavioral abnormalities characteristic of the Fragile X mental retardation syndrome result from the loss of function of the RNA-binding protein FMRP. The disease is usually caused by a triplet repeat expansion in the 5'UTR of the FMR1 gene. This leads to loss of function through transcriptional gene silencing, pointing to a key function for FMRP, but precluding genetic identification of critical activities within the protein. Moreover, antisense transcripts (FMR4, ASFMR1) in the same locus have been reported to be silenced by the repeat expansion. Missense mutations offer one means of confirming a central role for FMRP in the disease, but to date, only a single such patient has been described. This patient harbors an isoleucine to asparagine mutation (I304N) in the second FMRP KH-type RNA-binding domain, however, this single case report was complicated because the patient harbored a superimposed familial liver disease. To address these issues, we have generated a new Fragile X Syndrome mouse model in which the endogenous Fmr1 gene harbors the I304N mutation. These mice phenocopy the symptoms of Fragile X Syndrome in the existing Fmr1-null mouse, as assessed by testicular size, behavioral phenotyping, and electrophysiological assays of synaptic plasticity. I304N FMRP retains some functions, but has specifically lost RNA binding and polyribosome association; moreover, levels of the mutant protein are markedly reduced in the brain specifically at a time when synapses are forming postnatally. These data suggest that loss of FMRP function, particularly in KH2-mediated RNA binding and in synaptic plasticity, play critical roles in pathogenesis of the Fragile X Syndrome and establish a new model for studying the disorder."
- Bassell GJ & Warren ST. (2008). Fragile X syndrome: loss of local mRNA regulation alters synaptic development and function. Neuron , 60, 201-14. PMID: 18957214 DOI.
- Luo Y, Shan G, Guo W, Smrt RD, Johnson EB, Li X, Pfeiffer RL, Szulwach KE, Duan R, Barkho BZ, Li W, Liu C, Jin P & Zhao X. (2010). Fragile x mental retardation protein regulates proliferation and differentiation of adult neural stem/progenitor cells. PLoS Genet. , 6, e1000898. PMID: 20386739 DOI.
- Mor-Shaked H & Eiges R. (2018). Reevaluation ofFMR1Hypermethylation Timing in Fragile X Syndrome. Front Mol Neurosci , 11, 31. PMID: 29467618 DOI.
- van der Molen MJ, Stam CJ & van der Molen MW. (2014). Resting-state EEG oscillatory dynamics in fragile X syndrome: abnormal functional connectivity and brain network organization. PLoS ONE , 9, e88451. PMID: 24523898 DOI.
- Allen EG, Charen K, Hipp HS, Shubeck L, Amin A, He W, Hunter JE & Sherman SL. (2020). Clustering of comorbid conditions among women who carry an FMR1 premutation. Genet. Med. , , . PMID: 31896764 DOI.
- Hardiman RL & McGill P. (2018). How common are challenging behaviours amongst individuals with Fragile X Syndrome? A systematic review. Res Dev Disabil , , . PMID: 29525058 DOI.
- Klusek J, Martin GE & Losh M. (2014). Consistency between research and clinical diagnoses of autism among boys and girls with fragile X syndrome. J Intellect Disabil Res , 58, 940-52. PMID: 24528851 DOI.
- Dury AY, El Fatimy R, Tremblay S, Rose TM, Côté J, De Koninck P & Khandjian EW. (2013). Nuclear Fragile X Mental Retardation Protein is localized to Cajal bodies. PLoS Genet. , 9, e1003890. PMID: 24204304 DOI.
- Finucane B, Abrams L, Cronister A, Archibald AD, Bennett RL & McConkie-Rosell A. (2012). Genetic counseling and testing for FMR1 gene mutations: practice guidelines of the national society of genetic counselors. J Genet Couns , 21, 752-60. PMID: 22797890 DOI.
- Gocel J & Larson J. (2012). Synaptic NMDA receptor-mediated currents in anterior piriform cortex are reduced in the adult fragile X mouse. Neuroscience , 221, 170-81. PMID: 22750206 DOI.
- McConkie-Rosell A, Finucane B, Cronister A, Abrams L, Bennett RL & Pettersen BJ. (2005). Genetic counseling for fragile x syndrome: updated recommendations of the national society of genetic counselors. J Genet Couns , 14, 249-70. PMID: 16047089 DOI.
- Zang JB, Nosyreva ED, Spencer CM, Volk LJ, Musunuru K, Zhong R, Stone EF, Yuva-Paylor LA, Huber KM, Paylor R, Darnell JC & Darnell RB. (2009). A mouse model of the human Fragile X syndrome I304N mutation. PLoS Genet. , 5, e1000758. PMID: 20011099 DOI.
- Clinical Methods 3rd ed. Walker, H.K.; Hall, W.D.; Hurst, J.W.; editors Stoneham (MA): Butterworth Publishers; c1990 Table - Recognizable Genetic Conditions
- Modern Genetic Analysis Griffiths, Anthony J.F.; Gelbart, William M.; Miller, Jeffrey H.; Lewontin, Richard C. New York: W. H. Freeman & Co.; c1999.
- Introduction to Genetic Analysis 7th ed. Griffiths, Anthony J.F.; Miller, Jeffrey H.; Suzuki, David T.; Lewontin, Richard C.; Gelbart, William M. New York: W. H. Freeman & Co.; c1999.
Hagerman RJ, Berry-Kravis E, Hazlett HC, Bailey DB, Moine H, Kooy RF, Tassone F, Gantois I, Sonenberg N, Mandel JL & Hagerman PJ. (2017). Fragile X syndrome. Nat Rev Dis Primers , 3, 17065. PMID: 28960184 DOI.
van de Vondervoort II, Gordebeke PM, Khoshab N, Tiesinga PH, Buitelaar JK, Kozicz T, Aschrafi A & Glennon JC. (2013). Long non-coding RNAs in neurodevelopmental disorders. Front Mol Neurosci , 6, 53. PMID: 24415997 DOI.
Fung LK, Quintin EM, Haas BW & Reiss AL. (2012). Conceptualizing neurodevelopmental disorders through a mechanistic understanding of fragile X syndrome and Williams syndrome. Curr. Opin. Neurol. , 25, 112-24. PMID: 22395002 DOI.
Tranfaglia MR. (2011). The psychiatric presentation of fragile x: evolution of the diagnosis and treatment of the psychiatric comorbidities of fragile X syndrome. Dev. Neurosci. , 33, 337-48. PMID: 21893938 DOI.
Kim K, Hessl D, Randol JL, Espinal GM, Schneider A, Protic D, Aydin EY, Hagerman RJ & Hagerman PJ. (2019). Association between IQ and FMR1 protein (FMRP) across the spectrum of CGG repeat expansions. PLoS ONE , 14, e0226811. PMID: 31891607 DOI.
Haessler F, Gaese F, Colla M, Huss M, Kretschmar C, Brinkman M, Schieb H, Peters H, Elstner S & Pittrow D. (2013). EXPLAIN Fragile-X: an explorative, longitudinal study on the characterization, treatment pathways, and patient-related outcomes of Fragile X Syndrome. BMC Psychiatry , 13, 339. PMID: 24354947 DOI.
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- Australia - Fragile X Association of Australia
- USA - National Society of Genetic Counselors | National Fragile X Foundation
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Cite this page: Hill, M.A. (2020, July 3) Embryology Fragile X Syndrome. Retrieved from https://embryology.med.unsw.edu.au/embryology/index.php/Fragile_X_Syndrome
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