Frataxin knockin mouse

Abstract

Friedreich ataxia is the consequence of frataxin deficiency, most often caused by a GAA repeat expansion in intron 1 of the corresponding gene. Frataxin is a mitochondrial protein involved in iron homeostasis. As an attempt to generate a mouse model of the disease, we introduced a (GAA) 230 repeat within the mouse frataxin gene by homologous recombination. GAA repeat knockin mice were crossed with frataxin knockout mice to obtain double heterozygous mice expressing 25^36% of wild-type frataxin levels. These mice were viable and did not develop anomalies of motor coordination, iron metabolism or response to iron loading. Repeats were meiotically and mitotically stable. ß

Small molecules affecting transcription in Friedreich ataxia

“…Only after 12 months of age do the KIKO mice develop mild locomoter symptoms (M. Pandolfo, personal communication). Nonetheless, the FXN knock-in mouse provides an appropriate animal model for testing the in vivo efficacy of transcriptional activators: the KIKO mouse exhibits between 25 − 36% of wild-type FXN mRNA and protein in various organs, compared to wild-type mice (Miranda et al, 2002). These values lie within the range observed in mildly affected FRDA patients.…”

“…Three animal models are currently available for testing the in vivo efficacy of potential FXN activator molecules: these are the heterozygous [GAA·TTC] 230 KIKO (knock-in/knockout) and homozygous KIKI (knock-in) mice developed by Pandolfo and colleagues (Miranda et al, 2002), the human YAC FXN mouse developed by Pook and colleagues Clark et al, 2006), and the FXN-EGFP reporter mouse developed by Sarsero and colleagues (Sarsero et al, 2005;Sarsero et al, 2003). In the Pandolfo knock-in mice, a [GAA·TTC] 230 repeat was inserted into the mouse FXN locus at the position of the expansion in human FRDA alleles (FXN intron 1).…”

“…In the Pandolfo knock-in mice, a [GAA·TTC] 230 repeat was inserted into the mouse FXN locus at the position of the expansion in human FRDA alleles (FXN intron 1). However, this repeat knock-in does not reproduce an overt FRDA-like phenotype, although it does result in decreased frataxin RNA and protein (Miranda et al, 2002). Only after 12 months of age do the KIKO mice develop mild locomoter symptoms (M. Pandolfo, personal communication).…”

Friedreich Ataxia Mouse Models with Progressive Cerebellar and Sensory Ataxia Reveal Autophagic Neurodegeneration in Dorsal Root Ganglia

“…Several attempts have been made to produce an authentic model for the neurological symptoms of FRDA, but until now, no mouse model parallels the progressive neurological human disease Miranda et al, 2002). Through spatially and temporally controlled conditional FRDA gene inactivation, we have generated two different mouse models that developed the most prominent features of the human disease: a slowly progressive mixed cerebellar and sensory ataxia associated with a progressive loss of proprioception and absence of motor involvement.…”

Physiologically-Regulated Expression Vectors for Gene Therapy

“…The use of the entire genomic locus of the -globin gene cluster which included the locus control regions resulted in spatial and temporal expression profiles that mimicked the native profile (Porcu et al 1997;Vadolas, Wardan et al 2005). Further examples of the advantages of using the complete genomic locus comes from mice lacking either the frataxin (Fxn) gene (Cossee et al 2000;Miranda et al 2002) or the cystic fibrosis transmembrane conductance regulator (Cftr) gene (Zhou et al 1994;Manson et al 1997), mouse models of Friedrich's ataxia and cystic fibrosis, respectively. Mice lacking frataxin die at embryonic day six and crossing heterozygous knock-out mice with mice expressing the full genomic locus of the human FXN gene from a bacterial artificial chromosome (BAC) rescues the phenotype and expression patterns of mRNA and protein was physiological (Sarsero et al 2004).…”