Fragile X syndrome

Originally described by Martin and Bell in 1943, and sometimes referred to as Martin-Bell Syndrome. It is the most common X-linked form of mental retardation, and the second most common form of mental retardation after Down's syndrome. The phenotype of the fragile X syndrome (as it came to be most often known) includes moderate to severe mental retardation, hyperactivity, macroorchidism, large ears, prominent jaw, and high-pitched, jocular speech. Expression is variable, with mental retardation the most common feature. Both males and females can be affected, but females are usually not as severe in phenotype. There is an association in females with premature menopause (before age 40).

Most people with fragile X syndrome have a long trinucleotide repeat in the FMR1 gene that inhibits transcription. However, there are other mutations of FMR1 that give the same phenotype, but without evidence of a fragile site or broken chromosomes. So, the chromosome breakage is probably a secondary effect of the mutation rather than a primary cause of the mutant phenotype, and the primary cause of the mutant phenotype is altered or missing FMR1 protein.

The fragile site is a "secondary constriction" on the X (the primary constriction is the centromere), at Xq27-28. Its appearance is dependent on folate deficiency (which leads to a thymidine monophosphate deficiency). In heterozygotes, the fragile X is NOT preferentially inactivated; this accounts for phenotypic expression in females, half of whose cells will have an active fragile X chromosome.

Trinucleotide repeat (CGG). Also can be written as GCC. This TNR is in the 5' untranslated region of the FMR1 gene. Having between 6 and 50 repeats is the normal condition; such alleles are not unstable. Premutations, between 54 and 200 repeats, do not usually have a mutant phenotype, but they are unstable in meiosis (but not mitosis). The disease allele, 200-2000 repeats, is unstable both meiotically and mitotically, leading to mosaicism. Lymphoid cells are variable in the expression of the broken chromosome: in one experiment, 4 affected males were found to have broken X chromosomes in 17-50% of their lymphocytes.

The inheritance pattern often involves the "Sherman paradox": 20% of males with the fragile X chromosome are unaffected, and their daughters (who get the fragile X) are also unaffected. However, their grandsons and granddaughters often are affected. The explanation is that the original males had a "premutation": enough CGG repeats to be unstable in meiosis, but this instability only occurs in FEMALE meiosis; the premutation turns into a full fragile X mutation only when passed through a female parent.

Another aspect of the Sherman paradox is that daughters of affected males are not affected: the expansion of the TNR seems to occur in the embryo, not in the oocyte or the zygote, after the germ line cells have been segregated out. That is, even affected males only have the premutation in their germ line. I think this must also be true of females: only the premutation exists in the germ line, so their children have a risk of retardation, not a certainty.

Methylation of a CpG island near the repeat site, at the 5' end of the FMR1 gene, is involved: normal males who transmit the fragile X are unmethylated at this site, but males who are retarded due to having this chromosome have the site methylated. Also, the inactive X in females has this site methylated. The protein FMR1 isn't produced by methylated genes. 5-aza-dC treatment of cells can reactivate the gene. The current model holds that the TNR causes hypermethylation, and this in turn shuts off the FMR1 gene, causing the mutant phenotype.

The site does physically break, and this fact helped identify a clone containing the breakpoint: a fragment that exhibited length polymorphism. There are other fragile sites known, but none of them has an associated phenotype.

17 exons over 38 kb of chromosome, possibly some alternative splicing. Protein binds RNAs, including its own, in stoichiometric amounts (2 RNAs per protein) and with high affinity. The protein, FMR1, contains a nuclear translocation signal. Very active in all tissues of the embryo and fetus; in adults only active in the brain and testes

Some interesting population genetics is known: there are only a few haplotypes that develop the fragile X syndrome, and they can be used to trace lineages back thousands of years.

A mouse line with the Fmr-1 gene analogue knocked out has been created. These mice show macroorchidism, learning deficits, and hyperactivity.