Humpath.com - Human pathology

Home > A. Molecular pathology > FMR1

FMR1

Thursday 2 October 2003

Definition: The fragile X mental retardation 1 (FMR1) gene is primarily associated with neuro/psychiatric risks. The FMR1 gene is a regulator of ovarian recruitment and ovarian reserve. (20955631) FMR1 exerts controlling functions on follicle recruitment and ovarian reserve (OR). This function appears distinct from the gene’s neuro/psychiatric effects, associated with a different, and specific, triple nucleotide (CGG) repeat range and characterized by specific genotypes.

Ovarian function in all races/ethnicities appears defined by a normal range of 26 to 34 CGG repeats (mean 30), including the reported distribution peak of 29 to 30 repeats in humans and maximal gene translation, reported at 30 repeats.

Genotypes, defined by 2 normal count alleles (normal) demonstrate different OR aging patterns from women with 1 (heterozygous) or both alleles outside of range (homozygous). Heterozygous and homozygous genotypes recruit fewer follicles at younger ages, thus preserving OR into advanced age. These observations suggest a direct FMR1 effect on follicular recruitment and OR and, therefore, on women’s fecundity.

Pathology

- FMR1triplet repeats
- FMR1 conventional mutations

See also

- fragile X
- premature ovarian aging
- primary ovarian insufficiency
- occult primary ovarian insufficiency
- premature ovarian failure
- premature menopause
- ovarian reserve (OR)

  • diminished ovarian reserve
    - follicle recruitment
    - ovarian aging

Heterozygous and homozygous genotypes recruit fewer follicles at younger ages, thus preserving OR into advanced age. These observations suggest a direct FMR1 effect on follicular recruitment and OR and, therefore, on women’s fecundity.

Pathology

- Expansion of a CGG repeat in the 5’ untranslated region of the fragile X mental retardation 1 gene (FMR1) in fragile X mental retardation

- Male carriers of the FMR1 premutation are at risk of developing the fragile X-associated tremor/ataxia syndrome (FXTAS), a newly recognised and largely under-diagnosed late onset neurodegenerative disorder.

  • Patients affected with FXTAS primarily present with cerebellar ataxia and intention tremor.
  • Cognitive decline has also been associated with the premutation, but the lack of data on its penetrance is a growing concern for clinicians who provide genetic counselling.
  • Male carriers of midsize to large premutation alleles had a sixfold increased risk of developing cognitive decline and the risk increases with allele size. (19542082)
  • Cognitive impairment may precede motor symptoms. (19542082)

Reviews

- Oostra BA, Willemsen R. A fragile balance: FMR1 expression levels. Hum Mol Genet. 2003 Oct 15;12 Spec No 2:R249-57. PMID: 12952862

References

- The FMR1 gene as regulator of ovarian recruitment and ovarian reserve. Gleicher N, Barad DH. Obstet Gynecol Surv. 2010 Aug;65(8):523-30.PMID: 20955631

- Can the FMR1 gene predict early ovarian aging? Gleicher N, Barad DH. Womens Health (Lond Engl). 2010 Mar;6(2):165-9. PMID: 20187721 [Free]

- Penetrance of marked cognitive impairment in older male carriers of the FMR1 gene premutation. Sévin M, Kutalik Z, Bergman S, Vercelletto M, Renou P, Lamy E, Vingerhoets FJ, Di Virgilio G, Boisseau P, Bezieau S, Pasquier L, Rival JM, Beckmann JS, Damier P, Jacquemont S. J Med Genet. 2009 Dec;46(12):818-24. PMID: 19542082