Detection and Quantification of the Fragile X Mental Retardation Protein 1 (FMRP)

Overview

Journal Genes (Basel)

Publisher MDPI

Date 2016 Dec 13

PMID 27941672

Citations 13

Authors

Giuseppe LaFauci

Tatyana Adayev

Richard Kascsak

W Ted Brown

Affiliations

Soon will be listed here.

Abstract

The final product of gene transcription, Fragile X Mental Retardation Protein 1 (FMRP), is an RNA binding protein that acts as a repressor of translation. FMRP is expressed in several tissues and plays important roles in neurogenesis, synaptic plasticity, and ovarian functions and has been implicated in a number of neuropsychological disorders. The loss of FMRP causes Fragile X Syndrome (FXS). In most cases, FXS is due to large expansions of a CGG repeat in -normally containing 6-54 repeats-to over 200 CGGs and identified as full mutation (FM). Hypermethylation of the repeat induces silencing and lack of FMRP expression in FM male. Mosaic FM males express low levels of FMRP and present a less severe phenotype that inversely correlates with FMRP levels. Carriers of pre-mutations (55-200 CGG) show increased mRNA, and normal to reduced FMRP levels. Alternative splicing of mRNA results in 24 FMRP predicted isoforms whose expression are tissues and developmentally regulated. Here, we summarize the approaches used by several laboratories including our own to (a) detect and estimate the amount of FMRP in different tissues, developmental stages and various pathologies; and (b) to accurately quantifying FMRP for a direct diagnosis of FXS in adults and newborns.

Citing Articles

Variation of FMRP Expression in Peripheral Blood Mononuclear Cells from Individuals with Fragile X Syndrome.

Randol J, Kim K, Ponzini M, Tassone F, Falcon A, Hagerman R Genes (Basel). 2024; 15(3).

PMID: 38540415 PMC: 10969917. DOI: 10.3390/genes15030356.

The feasibility and utility of hair follicle sampling to measure FMRP and FMR1 mRNA in children with or without fragile X syndrome: a pilot study.

Jalnapurkar I, Frazier J, Roth M, Cochran D, Foley A, Merk T J Neurodev Disord. 2022; 14(1):57.

PMID: 36494616 PMC: 9733195. DOI: 10.1186/s11689-022-09465-7.

Optimization, validation and initial clinical implications of a Luminex-based immunoassay for the quantification of Fragile X Protein from dried blood spots.

Boggs A, Schmitt L, McLane R, Adayev T, LaFauci G, Horn P Sci Rep. 2022; 12(1):5617.

PMID: 35379866 PMC: 8980090. DOI: 10.1038/s41598-022-09633-8.

Fragile X Mental Retardation Protein and Cerebral Expression of Metabotropic Glutamate Receptor Subtype 5 in Men with Fragile X Syndrome: A Pilot Study.

Brasic J, Goodman J, Nandi A, Russell D, Jennings D, Barret O Brain Sci. 2022; 12(3).

PMID: 35326270 PMC: 8946825. DOI: 10.3390/brainsci12030314.

Experiences of the Molecular Diagnosis of Fragile X Syndrome in Ecuador.

Pozo-Palacios J, Llamos-Paneque A, Rivas C, Onofre E, Lopez-Caceres A, Villareal J Front Psychiatry. 2021; 12:716311.

PMID: 34966298 PMC: 8710471. DOI: 10.3389/fpsyt.2021.716311.

References

Tassone F, Hagerman R, Ikle D, Dyer P, Lampe M, Willemsen R . FMRP expression as a potential prognostic indicator in fragile X syndrome. Am J Med Genet. 1999; 84(3):250-61. View

Ericsson C, Nister M . Protein extraction from solid tissue. Methods Mol Biol. 2010; 675:307-12. DOI: 10.1007/978-1-59745-423-0_17. View

Willemsen R, Mohkamsing S, de Vries B, Devys D, van den Ouweland A, Mandel J . Rapid antibody test for fragile X syndrome. Lancet. 1995; 345(8958):1147-8. DOI: 10.1016/s0140-6736(95)90979-6. View

Hessl D, Wang J, Schneider A, Koldewyn K, Le L, Iwahashi C . Decreased fragile X mental retardation protein expression underlies amygdala dysfunction in carriers of the fragile X premutation. Biol Psychiatry. 2011; 70(9):859-65. PMC: 3191264. DOI: 10.1016/j.biopsych.2011.05.033. View

Willemsen R, Los F, Mohkamsing S, van den Ouweland A, Deelen W, GALJAARD H . Rapid antibody test for prenatal diagnosis of fragile X syndrome on amniotic fluid cells: a new appraisal. J Med Genet. 1997; 34(3):250-1. PMC: 1050903. DOI: 10.1136/jmg.34.3.250. View

Brouwer J, Mientjes E, Bakker C, Nieuwenhuizen I, Severijnen L, Van der Linde H . Elevated Fmr1 mRNA levels and reduced protein expression in a mouse model with an unmethylated Fragile X full mutation. Exp Cell Res. 2006; 313(2):244-53. PMC: 1852528. DOI: 10.1016/j.yexcr.2006.10.002. View

Kumari D, Bhattacharya A, Nadel J, Moulton K, Zeak N, Glicksman A . Identification of fragile X syndrome specific molecular markers in human fibroblasts: a useful model to test the efficacy of therapeutic drugs. Hum Mutat. 2014; 35(12):1485-94. PMC: 4287266. DOI: 10.1002/humu.22699. View

Tassone F, Iong K, Tong T, Lo J, Gane L, Berry-Kravis E . FMR1 CGG allele size and prevalence ascertained through newborn screening in the United States. Genome Med. 2012; 4(12):100. PMC: 4064316. DOI: 10.1186/gm401. View

Willemsen R, Hoogeveen-Westerveld M, Reis S, Holstege J, Severijnen L, Nieuwenhuizen I . The FMR1 CGG repeat mouse displays ubiquitin-positive intranuclear neuronal inclusions; implications for the cerebellar tremor/ataxia syndrome. Hum Mol Genet. 2003; 12(9):949-59. DOI: 10.1093/hmg/ddg114. View

10.

Devys D, Lutz Y, Rouyer N, Bellocq J, Mandel J . The FMR-1 protein is cytoplasmic, most abundant in neurons and appears normal in carriers of a fragile X premutation. Nat Genet. 1993; 4(4):335-40. DOI: 10.1038/ng0893-335. View

11.

Kaufmann W, Abrams M, Chen W, Reiss A . Genotype, molecular phenotype, and cognitive phenotype: correlations in fragile X syndrome. Am J Med Genet. 1999; 83(4):286-95. View

12.

Bidinosti M, Shimshek D, Mollenhauer B, Marcellin D, Schweizer T, Lotz G . Novel one-step immunoassays to quantify α-synuclein: applications for biomarker development and high-throughput screening. J Biol Chem. 2012; 287(40):33691-705. PMC: 3460466. DOI: 10.1074/jbc.M112.379792. View

13.

Schutzius G, Bleckmann D, Kapps-Fouthier S, di Giorgio F, Gerhartz B, Weiss A . A quantitative homogeneous assay for fragile X mental retardation 1 protein. J Neurodev Disord. 2013; 5(1):8. PMC: 3635944. DOI: 10.1186/1866-1955-5-8. View

14.

Berry-Kravis E, Abrams L, Coffey S, Hall D, Greco C, Gane L . Fragile X-associated tremor/ataxia syndrome: clinical features, genetics, and testing guidelines. Mov Disord. 2007; 22(14):2018-30, quiz 2140. DOI: 10.1002/mds.21493. View

15.

El Fatimy R, Tremblay S, Dury A, Solomon S, De Koninck P, Schrader J . Fragile X mental retardation protein interacts with the RNA-binding protein Caprin1 in neuronal RiboNucleoProtein complexes [corrected]. PLoS One. 2012; 7(6):e39338. PMC: 3380850. DOI: 10.1371/journal.pone.0039338. View

16.

Fatemi S, Folsom T . Dysregulation of fragile × mental retardation protein and metabotropic glutamate receptor 5 in superior frontal cortex of individuals with autism: a postmortem brain study. Mol Autism. 2011; 2:6. PMC: 3488976. DOI: 10.1186/2040-2392-2-6. View

17.

Seltzer M, Baker M, Hong J, Maenner M, Greenberg J, Mandel D . Prevalence of CGG expansions of the FMR1 gene in a US population-based sample. Am J Med Genet B Neuropsychiatr Genet. 2012; 159B(5):589-97. PMC: 3391968. DOI: 10.1002/ajmg.b.32065. View

18.

Brown V, Jin P, Ceman S, Darnell J, ODonnell W, Tenenbaum S . Microarray identification of FMRP-associated brain mRNAs and altered mRNA translational profiles in fragile X syndrome. Cell. 2001; 107(4):477-87. DOI: 10.1016/s0092-8674(01)00568-2. View

19.

Khandjian E, Fortin A, Thibodeau A, Tremblay S, Cote F, Devys D . A heterogeneous set of FMR1 proteins is widely distributed in mouse tissues and is modulated in cell culture. Hum Mol Genet. 1995; 4(5):783-9. DOI: 10.1093/hmg/4.5.783. View

20.

Cheever A, Blackwell E, Ceman S . Fragile X protein family member FXR1P is regulated by microRNAs. RNA. 2010; 16(8):1530-9. PMC: 2905753. DOI: 10.1261/rna.2022210. View