A transgenic mouse that carries the human Fragile-X (FMR1) gene: Neonatal lethality, Fragile-X protein expression and GABA-A receptor beta-subunit expression

Fragile X syndrome (FXS) is an inherited human disorder affecting approximately 1 in 4000 males. FXS arises from the silencing of a gene (FMR1) which is highly expressed in brain during normal development. Since this gene is located on the X chromosome, males are generally more severely affected than females. Mental retardation is the salient feature of FXS, but the syndrome is also associated with seizures and EEG irregularities. The FMR1 gene product (FMRP) appears to be an RNA binding protein and though it has been studied extensively, its cellular function and the means by which its absence affects cognition are unknown.; Mice carry an FMR1 homologue, (Fmr1), that is virtually identical to the human gene in protein sequence. Mutations have been engineered in the mouse in order to study the function of FMRP. One such mutation introduced 1–2 copies of human FMR1 as a transgene (TG). Expression of the transgene leads to reduced viability in females. Only 30% of the females derived from matings between heterozygous TG mice and wild-type mice which survived to the age of weaning were transgenic.; We have determined that this effect is specific to females and is the result of death during the first 24 hours after birth. Analysis of transgene expression in the neonatal brain indicates that the human protein is expressed at levels which are 10–15 greater than the murine homolog. We also examined the expression of the beta subunit of the GABA-A receptor, as this protein is reduced in mice which do not express the endogenous Fmr1 gene. We did not note any differences in the levels of this receptor between TG mice and WT mice.