FMR1

About FMR1

FMR1 on chromosome Xq27.3 encodes FMRP, the fragile X messenger ribonucleoprotein, an RNA binding protein that regulates local translation of messenger RNAs at synapses and is important for synaptic plasticity. The 5 prime untranslated region of the gene contains a CGG trinucleotide repeat. Alleles are classified as normal, intermediate, premutation with about 55 to 200 repeats, or full mutation with more than 200 repeats. Full mutations become methylated, silencing the gene and causing fragile X syndrome, the most common inherited cause of intellectual disability, which affects males more often and more severely than females. Features include intellectual disability, autistic features, anxiety, a long face, large ears, joint laxity, enlarged testes after puberty, and sometimes seizures. Premutation carriers do not have fragile X syndrome but produce excess FMR1 RNA that can be toxic, and some develop fragile X associated tremor ataxia syndrome later in life, while some female carriers develop fragile X associated primary ovarian insufficiency. Premutations can expand to full mutations when passed on by mothers. The fragile site on the X chromosome was described in 1969, and the gene was identified in 1991, one of the first examples of a trinucleotide repeat disease. Targeted treatments are being studied in clinical trials.