2fmr

Structural highlights

Disease

[FMR1_HUMAN] Defects in FMR1 are the cause of fragile X syndrome (FRAX) [MIM:300624]. Fragile X syndrome is a common genetic disease (has a prevalence of one in every 2000 children) which is characterized by moderate to severe mental retardation, macroorchidism (enlargement of the testicles), large ears, prominent jaw, and high-pitched, jocular speech. The defect in most fragile X syndrome patients results from an amplification of a CGG repeat region which is directly in front of the coding region.^{[1] [2] [3] [4] [5] [6] [7] [8]} Defects in FMR1 are the cause of fragile X tremor/ataxia syndrome (FXTAS) [MIM:300623]. In FXTAS, the expanded repeats range in size from 55 to 200 repeats and are referred to as 'premutations'. Full repeat expansions with greater than 200 repeats results in fragile X mental retardation syndrome [MIM:300624]. Carriers of the premutation typically do not show the full fragile X syndrome phenotype, but comprise a subgroup that may have some physical features of fragile X syndrome or mild cognitive and emotional problems.^[9] Defects in FMR1 are the cause of premature ovarian failure syndrome type 1 (POF1) [MIM:311360]. An ovarian disorder defined as the cessation of ovarian function under the age of 40 years. It is characterized by oligomenorrhea or amenorrhea, in the presence of elevated levels of serum gonadotropins and low estradiol.^[10]

Function

[FMR1_HUMAN] Translation repressor. Component of the CYFIP1-EIF4E-FMR1 complex which binds to the mRNA cap and mediates translational repression. In the CYFIP1-EIF4E-FMR1 complex this subunit mediates translation repression (By similarity). RNA-binding protein that plays a role in intracellular RNA transport and in the regulation of translation of target mRNAs. Associated with polysomes. May play a role in the transport of mRNA from the nucleus to the cytoplasm. Binds strongly to poly(G), binds moderately to poly(U) but shows very little binding to poly(A) or poly(C).

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

References

1. ↑ Linder B, Plottner O, Kroiss M, Hartmann E, Laggerbauer B, Meister G, Keidel E, Fischer U. Tdrd3 is a novel stress granule-associated protein interacting with the Fragile-X syndrome protein FMRP. Hum Mol Genet. 2008 Oct 15;17(20):3236-46. doi: 10.1093/hmg/ddn219. Epub 2008 Jul, 28. PMID:18664458 doi:10.1093/hmg/ddn219
2. ↑ Devys D, Lutz Y, Rouyer N, Bellocq JP, Mandel JL. The FMR-1 protein is cytoplasmic, most abundant in neurons and appears normal in carriers of a fragile X premutation. Nat Genet. 1993 Aug;4(4):335-40. PMID:8401578 doi:http://dx.doi.org/10.1038/ng0893-335
3. ↑ Siomi H, Siomi MC, Nussbaum RL, Dreyfuss G. The protein product of the fragile X gene, FMR1, has characteristics of an RNA-binding protein. Cell. 1993 Jul 30;74(2):291-8. PMID:7688265
4. ↑ Valverde R, Pozdnyakova I, Kajander T, Venkatraman J, Regan L. Fragile X mental retardation syndrome: structure of the KH1-KH2 domains of fragile X mental retardation protein. Structure. 2007 Sep;15(9):1090-8. PMID:17850748 doi:http://dx.doi.org/10.1016/j.str.2007.06.022
5. ↑ De Boulle K, Verkerk AJ, Reyniers E, Vits L, Hendrickx J, Van Roy B, Van den Bos F, de Graaff E, Oostra BA, Willems PJ. A point mutation in the FMR-1 gene associated with fragile X mental retardation. Nat Genet. 1993 Jan;3(1):31-5. PMID:8490650 doi:http://dx.doi.org/10.1038/ng0193-31
6. ↑ Verheij C, de Graaff E, Bakker CE, Willemsen R, Willems PJ, Meijer N, Galjaard H, Reuser AJ, Oostra BA, Hoogeveen AT. Characterization of FMR1 proteins isolated from different tissues. Hum Mol Genet. 1995 May;4(5):895-901. PMID:7633450
7. ↑ Feng Y, Absher D, Eberhart DE, Brown V, Malter HE, Warren ST. FMRP associates with polyribosomes as an mRNP, and the I304N mutation of severe fragile X syndrome abolishes this association. Mol Cell. 1997 Dec;1(1):109-18. PMID:9659908
8. ↑ Darnell JC, Fraser CE, Mostovetsky O, Stefani G, Jones TA, Eddy SR, Darnell RB. Kissing complex RNAs mediate interaction between the Fragile-X mental retardation protein KH2 domain and brain polyribosomes. Genes Dev. 2005 Apr 15;19(8):903-18. Epub 2005 Apr 1. PMID:15805463 doi:gad.1276805
9. ↑ Hagerman RJ, Leehey M, Heinrichs W, Tassone F, Wilson R, Hills J, Grigsby J, Gage B, Hagerman PJ. Intention tremor, parkinsonism, and generalized brain atrophy in male carriers of fragile X. Neurology. 2001 Jul 10;57(1):127-30. PMID:11445641
10. ↑ Murray A, Webb J, Grimley S, Conway G, Jacobs P. Studies of FRAXA and FRAXE in women with premature ovarian failure. J Med Genet. 1998 Aug;35(8):637-40. PMID:9719368