Regional FMRP deficits and large repeat expansions into the full mutation range in a new Fragile X premutation mouse model

• Published in: Gene Vol. 395; no. 1; pp. 125 - 134
• Main Authors: Entezam, Ali, Biacsi, Rea, Orrison, Bonnie, Saha, Tapas, Hoffman, Gloria E., Grabczyk, Ed, Nussbaum, Robert L., Usdin, Karen
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 15.06.2007
• Subjects: 5' Untranslated Regions; Alleles; Animals; Base Sequence; Brain - metabolism; Disease Models, Animal; DNA instability; DNA Methylation; DNA Repeat Expansion; Female; Fragile X Mental Retardation Protein - genetics; Fragile X Mental Retardation Protein - metabolism; Fragile X Syndrome - genetics; Fragile X Syndrome - metabolism; Fragile X Syndrome - physiopathology; Full mutation; Gene Targeting; Genomic Instability; Humans; Male; Mice; Mice, Mutant Strains; Mutation; Repeat expansion; RNA, Messenger - genetics; RNA, Messenger - metabolism; FXS; FMRP; FMR1; CNS; Repeat expansion; bp; ES; DNA instability; FXTAS; kb; YAC; Full mutation; WT; KI; PCR; Nm
• ISSN: 0378-1119; 1879-0038
• DOI: 10.1016/j.gene.2007.02.026

Carriers of FMR1 alleles with 55–200 repeats in the 5′ UTR are at risk for Fragile X associated tremor and ataxia syndrome. The cause of the neuropathology is unknown but is thought to be RNA-mediated. Maternally transmitted premutation alleles are also at risk of expansion of the repeat tract into the “full mutation” range (> 200 repeats). The mechanism responsible for expansion is unknown. Full mutation alleles produce reduced amounts of the FMR1 gene product, FMRP, which leads to Fragile X mental retardation syndrome. We have developed a murine model for Fragile X premutation carriers that recapitulates key features seen in humans including a direct relationship between repeat number and Fmr1 mRNA levels, an inverse relationship with FMRP levels and Purkinje cell dropout that have not been seen in a previously described knock-in mouse model. In addition, these mice also show a differential deficit of FMRP in different parts of the brain that might account for symptoms of the full mutation that are seen in premutation carriers. As in humans, repeat instability is high with expansions predominating and, for the first time in a mouse model, large expansions into the full mutation range are seen that occur within a single generation. Thus, contrary to what was previously thought, mice may be good models not only for the symptoms seen in human carriers of FMR1 premutation alleles but also for understanding the mechanism responsible for repeat expansion, a phenomenon that is responsible for a number of neurological and neurodevelopmental disorders.