title: Somatic instability of the expanded GAA triplet-repeat sequence in Friedreich ataxia progresses throughout life.
abstract: Friedreich ataxia (FRDA) patients are homozygous for expanded GAA triplet-repeat alleles in the FXN gene. Primary neurodegeneration involving the dorsal root ganglia (DRG) results in progressive ataxia. While it is known that DRG are inherently sensitive to frataxin deficiency, recent observations also indicate that they show age-dependent, further expansion of the GAA triplet-repeat mutation. Whether somatic instability is progressive has not been systematically investigated in FRDA patients. "Small-pool" PCR analysis of approximately 2300 individual molecules from tissues of an 18-week fetus homozygous for expanded alleles revealed very low levels of instability compared with adult-derived tissues (4.2% versus 30.6%, p<0.0001). Mutation load in blood samples from multiple patients and carriers increased significantly with age, ranging from 7.5% at 18-weeks gestation to 78.7% at 49 years of age (R=0.91; p=0.0001). Therefore, somatic instability in FRDA occurs mostly after early embryonic development and progresses throughout life, lending further support to the role of postnatal somatic instability in disease pathogenesis.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
authors.forename: Irene
authors.initials: I
authors.lastname: De Biase
authors.forename: Astrid
authors.initials: A
authors.lastname: Rasmussen
authors.forename: Antonella
authors.initials: A
authors.lastname: Monticelli
authors.forename: Sahar
authors.initials: S
authors.lastname: Al-Mahdawi
authors.forename: Mark
authors.initials: M
authors.lastname: Pook
authors.forename: Sergio
authors.initials: S
authors.lastname: Cocozza
authors.forename: Sanjay I
authors.initials: SI
authors.lastname: Bidichandani
mesh_terms: D047108:Embryonic Development / Q000235:genetics; D005621:Friedreich Ataxia / Q000235:genetics*; D006801:Humans; D033862:Iron-Binding Proteins / Q000235:genetics*; D053842:Microsatellite Instability; D013997:Time Factors; D018911:Trinucleotide Repeats / Q000235:genetics*; D000096923:Frataxin
chemical_list: D033862:Iron-Binding Proteins; D000096923:Frataxin