The FMR1 gene provides instructions for making a protein called FMRP. This protein is present in many tissues, including the brain, testes, and ovaries. In the brain, it may play a role in the development of connections between nerve cells (synapses), where cell-to-cell communication occurs. The synapses can change and adapt over time in response to experience (a characteristic called synaptic plasticity). FMRP may help regulate synaptic plasticity, which is important for learning and memory. The protein's role in the testes and ovaries is not well understood.
Researchers believe that FMRP acts as a shuttle within cells by transporting molecules called messenger RNA (mRNA), which serve as the genetic blueprint for making proteins. FMRP likely carries mRNA molecules from the nucleus to areas of the cell where proteins are assembled. FMRP also helps control when the instructions in these mRNA molecules are used to build proteins, some of which may be important for functioning of the nerves, testes, or ovaries.
One region of the FMR1 gene contains a particular DNA segment known as a CGG trinucleotide repeat, so called because this segment of three DNA building blocks (nucleotides) is repeated multiple times within the gene. In most people, the number of CGG repeats ranges from fewer than 10 to about 40. This CGG repeat segment is typically interrupted several times by a different three-base sequence, AGG. Having AGG scattered among the CGG triplets appears to help stabilize the long repeated segment.
Health Conditions Related to Genetic Changes
Fragile X-associated primary ovarian insufficiency
A trinucleotide repeat expansion in the FMR1 gene increases a woman's risk of developing a condition called fragile X-associated primary ovarian insufficiency (FXPOI). In this condition, the CGG trinucleotide repeat in the FMR1 gene is repeated about 55 to 200 times, which is referred to as a premutation. Women who develop FXPOI may experience irregular menstrual cycles, an inability to have children (infertility), early menopause, and elevated levels of a hormone known as follicle stimulating hormone (FSH). About 16 to 20 percent of women with a premutation have FXPOI, which leads to abnormal menstrual cycles and elevated FSH levels before age 40 and often causes infertility.
For unknown reasons, the premutation leads to the overproduction of abnormal FMR1 mRNA that contains the repeat expansion. Researchers believe that the abnormal mRNA causes the signs and symptoms of FXPOI. It is thought that the mRNA attaches (binds) to other proteins and keeps them from performing their functions. In addition, the repeats make producing protein from the blueprint more difficult, and consequently, some people with the FMR1 gene premutation have lower than normal amounts of FMRP. As a result, they may have mild versions of the physical features seen in fragile X syndrome (described above), such as prominent ears, and may experience emotional problems such as anxiety or depression.More About This Health Condition
Fragile X-associated tremor/ataxia syndrome
Men, and some women, with an FMR1 gene premutation are at increased risk of developing a disorder known as fragile X-associated tremor/ataxia syndrome (FXTAS). FXTAS is characterized by progressive problems with movement (ataxia), tremor, memory loss, reduced sensation in the lower extremities (peripheral neuropathy), and mental and behavioral changes. The disorder usually develops late in life and worsens over time.
As in FXPOI (described above), the premutation causes overproduction of abnormal FMR1 mRNA containing the expanded repeat region, and researchers believe that this abnormal mRNA causes FXTAS. The abnormal mRNA has been found in clumps of proteins and mRNA (intranuclear inclusions) that are found in brain and nerve cells in people with FXTAS. Some researchers speculate that the proteins found in the inclusions cannot perform their normal functions, which could lead to the signs and symptoms of FXTAS. Another hypothesis is that the inclusions could cause the death of nerve cells important for movement and mental function. However, the exact role the inclusions play in the development of the disorder is unknown.More About This Health Condition
Fragile X syndrome
Almost all cases of fragile X syndrome are caused by an expansion of the CGG trinucleotide repeat in the FMR1 gene. In these cases, CGG is abnormally repeated more than 200 times, which makes this region of the gene unstable. As a result, the FMR1 gene is turned off (silenced) and makes very little or no protein. A loss or shortage of FMRP disrupts normal functions of nerve cells and, consequently, the nervous system, causing severe learning problems, intellectual disability, and the other features of fragile X syndrome. About one-third of males with an FMR1 gene mutation and the characteristic signs of fragile X syndrome also have features of autism spectrum disorders that affect communication and social interaction.
Fewer than 1 percent of all cases of fragile X syndrome are caused by other changes in the FMR1 gene. Mutations may delete part or all of the gene or change one of the building blocks (amino acids) used to make FMRP. These genetic changes alter the 3-dimensional shape of the protein or prevent any protein from being produced. The abnormal or missing protein disrupts nervous system functions, leading to the signs and symptoms of fragile X syndrome.More About This Health Condition
The FMR1 gene premutation (55 to 200 CGG repeats) is associated with a variety of neurological problems grouped as fragile X-associated neuropsychiatric disorders (FXAND). Children with a premutation can have learning disabilities, attention-deficit/hyperactivity disorder (ADHD), intellectual disability, or developmental disorders that affect communication and social interaction (such as autism spectrum disorder). Some adults with a premutation have emotional or psychiatric problems, such as depression, anxiety, obsessive-compulsive disorder, extreme tiredness (fatigue), chronic pain, or difficulty sleeping (insomnia). It is estimated that approximately half of people with a premutation have one or more of these problems. The neuropsychiatric abnormalities are thought to be caused by an abundance of abnormal FMR1 mRNA that impairs the function of other proteins.
Other Names for This Gene
- Protein FMR-1
Additional Information & Resources
Tests Listed in the Genetic Testing Registry
Scientific Articles on PubMed
Catalog of Genes and Diseases from OMIM
- Bretherick KL, Fluker MR, Robinson WP. FMR1 repeat sizes in the gray zone and high end of the normal range are associated with premature ovarian failure. Hum Genet. 2005 Aug;117(4):376-82. doi: 10.1007/s00439-005-1326-8. Epub 2005 Jun 2. Citation on PubMed
- Hagerman R, Hagerman P. Advances in clinical and molecular understanding of the FMR1 premutation and fragile X-associated tremor/ataxia syndrome. Lancet Neurol. 2013 Aug;12(8):786-98. doi: 10.1016/S1474-4422(13)70125-X. Citation on PubMed or Free article on PubMed Central
- Hagerman RJ, Berry-Kravis E, Hazlett HC, Bailey DB Jr, Moine H, Kooy RF, Tassone F, Gantois I, Sonenberg N, Mandel JL, Hagerman PJ. Fragile X syndrome. Nat Rev Dis Primers. 2017 Sep 29;3:17065. doi: 10.1038/nrdp.2017.65. Citation on PubMed
- Hagerman RJ, Protic D, Rajaratnam A, Salcedo-Arellano MJ, Aydin EY, Schneider A. Fragile X-Associated Neuropsychiatric Disorders (FXAND). Front Psychiatry. 2018 Nov 13;9:564. doi: 10.3389/fpsyt.2018.00564. eCollection 2018. Citation on PubMed or Free article on PubMed Central
- Hessl D, Wang JM, Schneider A, Koldewyn K, Le L, Iwahashi C, Cheung K, Tassone F, Hagerman PJ, Rivera SM. Decreased fragile X mental retardation protein expression underlies amygdala dysfunction in carriers of the fragile X premutation. Biol Psychiatry. 2011 Nov 1;70(9):859-65. doi: 10.1016/j.biopsych.2011.05.033. Epub 2011 Jul 23. Citation on PubMed or Free article on PubMed Central
- Hunsaker MR, Greco CM, Spath MA, Smits AP, Navarro CS, Tassone F, Kros JM, Severijnen LA, Berry-Kravis EM, Berman RF, Hagerman PJ, Willemsen R, Hagerman RJ, Hukema RK. Widespread non-central nervous system organ pathology in fragile X premutation carriers with fragile X-associated tremor/ataxia syndrome and CGG knock-in mice. Acta Neuropathol. 2011 Oct;122(4):467-79. doi: 10.1007/s00401-011-0860-9. Epub 2011 Jul 23. Citation on PubMed or Free article on PubMed Central
- Hunter JE, Berry-Kravis E, Hipp H, Todd PK. FMR1 Disorders. 1998 Jun 16 [updated 2019 Nov 21]. In: Adam MP, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(R) [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2023. Available from http://www.ncbi.nlm.nih.gov/books/NBK1384/ Citation on PubMed
- 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. Penetrance of the fragile X-associated tremor/ataxia syndrome in a premutation carrier population. JAMA. 2004 Jan 28;291(4):460-9. doi: 10.1001/jama.291.4.460. Citation on PubMed
- Kim K, Hessl D, Randol JL, Espinal GM, Schneider A, Protic D, Aydin EY, Hagerman RJ, Hagerman PJ. Association between IQ and FMR1 protein (FMRP) across the spectrum of CGG repeat expansions. PLoS One. 2019 Dec 31;14(12):e0226811. doi: 10.1371/journal.pone.0226811. eCollection 2019. Citation on PubMed or Free article on PubMed Central
- Li Y, Jin P. RNA-mediated neurodegeneration in fragile X-associated tremor/ataxia syndrome. Brain Res. 2012 Jun 26;1462:112-7. doi: 10.1016/j.brainres.2012.02.057. Epub 2012 Mar 9. Citation on PubMed or Free article on PubMed Central
- Ma L, Herren AW, Espinal G, Randol J, McLaughlin B, Martinez-Cerdeno V, Pessah IN, Hagerman RJ, Hagerman PJ. Composition of the Intranuclear Inclusions of Fragile X-associated Tremor/Ataxia Syndrome. Acta Neuropathol Commun. 2019 Sep 3;7(1):143. doi: 10.1186/s40478-019-0796-1. Citation on PubMed or Free article on PubMed Central
- Tassone F, Beilina A, Carosi C, Albertosi S, Bagni C, Li L, Glover K, Bentley D, Hagerman PJ. Elevated FMR1 mRNA in premutation carriers is due to increased transcription. RNA. 2007 Apr;13(4):555-62. doi: 10.1261/rna.280807. Epub 2007 Feb 5. Citation on PubMed or Free article on PubMed Central
- Todd PK, Oh SY, Krans A, He F, Sellier C, Frazer M, Renoux AJ, Chen KC, Scaglione KM, Basrur V, Elenitoba-Johnson K, Vonsattel JP, Louis ED, Sutton MA, Taylor JP, Mills RE, Charlet-Berguerand N, Paulson HL. CGG repeat-associated translation mediates neurodegeneration in fragile X tremor ataxia syndrome. Neuron. 2013 May 8;78(3):440-55. doi: 10.1016/j.neuron.2013.03.026. Epub 2013 Apr 18. Erratum In: Neuron. 2013 Jul 24;79(2):402. Citation on PubMed or Free article on PubMed Central
- Wang JY, Hessl D, Hagerman RJ, Simon TJ, Tassone F, Ferrer E, Rivera SM. Abnormal trajectories in cerebellum and brainstem volumes in carriers of the fragile X premutation. Neurobiol Aging. 2017 Jul;55:11-19. doi: 10.1016/j.neurobiolaging.2017.03.018. Epub 2017 Mar 18. Citation on PubMed or Free article on PubMed Central
- Wheeler A, Raspa M, Hagerman R, Mailick M, Riley C. Implications of the FMR1 Premutation for Children, Adolescents, Adults, and Their Families. Pediatrics. 2017 Jun;139(Suppl 3):S172-S182. doi: 10.1542/peds.2016-1159D. Citation on PubMed or Free article on PubMed Central
- Wittenberger MD, Hagerman RJ, Sherman SL, McConkie-Rosell A, Welt CK, Rebar RW, Corrigan EC, Simpson JL, Nelson LM. The FMR1 premutation and reproduction. Fertil Steril. 2007 Mar;87(3):456-65. doi: 10.1016/j.fertnstert.2006.09.004. Epub 2006 Oct 30. Citation on PubMed