Premature Ovarian Failure 1 (FMR1)
| Dred_ID | RD00037 |
| OMIM ID | 311360 |
| Disease name | Premature Ovarian Failure 1 |
| Alternative names | Premature Ovarian Failure, X-linked Pofx Hypergonadotropic Ovarian Failure, X-linked Ovarian Failure, Premature Pof Pof1 |
| Category | Genetic diseases, Endocrine diseases, Reproductive diseases |
| Phenotype | Premature ovarian failure is clearly a heterogeneous disorder. The terms 'hypergonadotropic ovarian failure' and 'hypergonadotropic ovarian dysgenesis' (see ODG1, 233300) have been used to indicate a group of disorders in which amenorrhea associated with elevated levels of serum gonadotropins occurs long before the age of 40 years (Coulam, 1982). Cytogenetic studies of X-chromosome aberrations have suggested that it is mainly the long arm of the X chromosome that is involved in defects of ovulation |
| Miscellaneouse | OMIM: Premature ovarian failure is clearly a heterogeneous disorder. The terms 'hypergonadotropic ovarian failure' and 'hypergonadotropic ovarian dysgenesis' (see ODG1, 233300) have been used to indicate a group of disorders in which amenorrhea associated with elevated levels of serum gonadotropins occurs long before the age of 40 years (Coulam, 1982). Cytogenetic studies of X-chromosome aberrations have suggested that it is mainly the long arm of the X chromosome that is involved in defects of ovulation (Bione et al., 1998). |
| Prevalence | N/A [source: MalaCards] |
| Inheritance | X-linked inheritance |
| Anticipation | Yes |
| Evidence | Strong |
| Gene symbol | FMR1 |
| Alias symbols | POF; FMRP; POF1; FRAXA |
| Gene name | FMR1 fragile X mental retardation 1 |
| Gene map locus | Xq27.3; 147,911,919-147,951,125(+) |
| Ensembl Gene ID | ENSG00000102081 |
| Gene expression and Gene Ontology | BioGPS |
| Protein expression | Human Protein Atlas |
| Gene sequence | Sequence |
| Variation | ClinVar, dbSNP | Gene conservation | Gene Conservation from UCSC Genome Browser |
| Gene Description | The protein encoded by this gene binds RNA and is associated with polysomes. The encoded protein may be involved in mRNA trafficking from the nucleus to the cytoplasm. A trinucleotide repeat (CGG) in the 5' UTR is normally found at 6-53 copies, but an expansion to 55-230 repeats is the cause of fragile X syndrome. Expansion of the trinucleotide repeat may also cause one form of premature ovarian failure (POF1). Multiple alternatively spliced transcript variants that encode different protein isoforms and which are located in different cellular locations have been described for this gene. [provided by RefSeq, May 2010] |
| Repeat unit | CGG |
| Normal repeat copies | 5-44 |
| Pathogenic repeat copies | 55-200 |
| Gene | FMR1 |
| Repeat location | 5' UTR |
| Chromosome locus | chrX:147912051-147912113 (+) |
| Repeat conservation | Repeat Conservation from UCSC Genome Browser |
| Toxic cause | RNA |
| Possible toxicity | Regarding FMR1 premutation carriers specifically, it should be noted that, other than the risk of expansion in subsequent generations, they also display a diverse spectrum of health disorders, entailing wide and impactful implications for the proband and family members of all ages. Notably, premutation is associated with premature ovarian failure (POF1) and fragile X-associated tremor/ataxia syndrome (FXTAS). Contrary to FXS, the pathophysiological bases of the disorders associated with FMR1 premutation appear to be related to a significant increase in FMR1 transcript, which has been suggested to cause a toxic gain-of-function effect due to mRNA–protein interactions that lead to aberrant protein synthesis and sequestration in the cytoplasm. More specifically, they hypothesized that expanded CGG repeats might lead to the formation of dynamic intra-nuclear long rCGG RNA aggregates capable of binding and sequestering crucial RNA binding proteins. In particular, proteins such as Sam68 and DGCR8, and its partner DROSHA, have been shown to bind directly to the double-stranded RNA hairpin structure of long rCGG RNA aggregates, causing severe impairment of normal cell function and ultimately cell death. In women with 70 to 120 repeats, who display the most severe forms of POF1, the accumulation of FMR1 mRNA in granulosa cells has been hypothesized to be responsible for disrupting ovarian function.[By PMID:38275588] |
| Pathway annotation | Reactome, KEGG |
| PMID | 23703681 |
| Authors | Murray A, Schoemaker MJ, Bennett CE, Ennis S, Macpherson JN, Jones M, Morris DH, Orr N, Ashworth A, Jacobs PA, Swerdlow AJ |
| Title | Population-based estimates of the prevalence of FMR1 expansion mutations in women with early menopause and primary ovarian insufficiency |
| Journal | Genet. Med. 16: 19-24 |
| Year | 2014 |