FMR1

FMR1 is a gene on the X chromosome (location Xq27.3) that encodes the fragile X mental retardation protein (FMRP). FMRP is an RNA-binding protein involved in transporting and regulating the translation of multiple neuronal mRNAs at synapses, a function that influences synaptic development and plasticity.

The phenotypes associated with FMR1 mutations depend on the length of the CGG trinucleotide repeat in the 5' untranslated region of the gene. Normal alleles typically have up to about 44 repeats. Grey-zone alleles are 45–54 repeats. Premutations range from about 55 to 200 repeats and are associated with elevated FMR1 mRNA levels; full mutations exceed 200 repeats and lead to methylation and silencing of FMR1, resulting in little to no FMRP production.

Fragile X syndrome, caused by a full mutation, is the most common inherited cause of intellectual disability and a frequent single-gene cause of autism spectrum disorder. Features can include developmental delay, intellectual disability of varying severity, distinctive facial features, macroorchidism after puberty, sensory hypersensitivity, and behavioral challenges such as anxiety or ADHD. Female carriers may have milder cognitive or emotional symptoms due to X-inactivation.

Premutations are associated with Fragile X-associated tremor/ataxia syndrome (FXTAS) in some older carriers and with Fragile X-associated premature ovarian insufficiency (FXPOI) in some female carriers. Diagnosis is via molecular genetic testing to determine CGG repeat size and methylation status, usually by PCR and Southern blot. There is no cure for Fragile X syndrome; management emphasizes developmental support, education, speech and occupational therapy, and treatment of coexisting conditions. Research continues into targeted therapies addressing the dysregulated protein synthesis linked to FMRP loss.