Abstract

Friedreich ataxia is an autosomal recessive disease, characterized clinically by ataxia (incoordination), cardiomyopathy and diabetes. The most common mutation, seen in >95% of patients is an abnormal expansion of a GAA triplet-repeat sequence in intron 1 of the FRDA (frataxin) gene. Normal and mutant alleles contain 6 - 100 and 100 - 1700 triplets, respectively. Expanded (mutant) alleles exhibit marked instability in somatic cells and during intergenerational transmission. Disease-causing expansions arise when premutation alleles (30 - 100 triplets) undergo hyperexpansion during intergenerational transmission. The mechanism of hyperexpansion of premutation alleles and the subsequent somatic and germline instability of expanded alleles remains poorly understood. The overall goal of this project is to investigate the mutagenic mechanisms underlying the genetic instability of the GAA triplet-repeat sequence. We will perform """"""""small-pool PCR"""""""" (SP-PCR) analysis to test the pattern of genetic instability of normal, premutation, and expanded chromosomes, in a wide variety of somatic tissues and germ cells derived from patients and asymptomatic carriers of various alleles. We will investigate the effect of DNA replication on GAA triplet-repeat instability using a defined eukaryotic replication model system. We will also investigate the role of cis-acting and epigenetic modifiers in determining instability of the GAA triplet-repeat sequence. It is hoped that these studies will lead to the development of novel strategies to prevent or reverse the process of GAA triplet-repeat expansion as a possible future therapy for Friedreich ataxia. Our data could potentially lead to the discovery of general properties of triplet-repeat instability, which will have implications for other diseases caused by this mutational mechanism.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS047596-01
Application #
6718704
Study Section
Mammalian Genetics Study Section (MGN)
Program Officer
Gwinn, Katrina
Project Start
2004-01-01
Project End
2007-12-31
Budget Start
2004-01-01
Budget End
2004-12-31
Support Year
1
Fiscal Year
2004
Total Cost
$269,907
Indirect Cost

  Institution

Name
University of Oklahoma Health Sciences Center
Department
Biochemistry
Type
Schools of Medicine
DUNS #
878648294
City
Oklahoma City
State
OK
Country
United States
Zip Code
73117

  Publications

Ezzatizadeh, Vahid; Pinto, Ricardo Mouro; Sandi, Chiranjeevi et al. (2012) The mismatch repair system protects against intergenerational GAA repeat instability in a Friedreich ataxia mouse model. Neurobiol Dis 46:165-71
Bourn, Rebecka L; De Biase, Irene; Pinto, Ricardo Mouro et al. (2012) Pms2 suppresses large expansions of the (GAA·TTC)n sequence in neuronal tissues. PLoS One 7:e47085
Rindler, Paul M; Bidichandani, Sanjay I (2011) Role of transcript and interplay between transcription and replication in triplet-repeat instability in mammalian cells. Nucleic Acids Res 39:526-35
Bourn, Rebecka L; Rindler, Paul M; Pollard, Laura M et al. (2009) E. coli mismatch repair acts downstream of replication fork stalling to stabilize the expanded (GAA.TTC)(n) sequence. Mutat Res 661:71-7
Rasmussen, Astrid; De Biase, Irene; Fragoso-Benitez, Marcela et al. (2007) Anticipation and intergenerational repeat instability in spinocerebellar ataxia type 17. Ann Neurol 61:607-10
Alonso, Elisa; Martinez-Ruano, Leticia; De Biase, Irene et al. (2007) Distinct distribution of autosomal dominant spinocerebellar ataxia in the Mexican population. Mov Disord 22:1050-3
De Biase, Irene; Rasmussen, Astrid; Endres, Dan et al. (2007) Progressive GAA expansions in dorsal root ganglia of Friedreich's ataxia patients. Ann Neurol 61:55-60
Rasmussen, A; Gomez, M; Alonso, E et al. (2006) Clinical heterogeneity of recessive ataxia in the Mexican population. J Neurol Neurosurg Psychiatry 77:1370-2
Clark, Rhonda M; Bhaskar, Sanjeev S; Miyahara, Masaki et al. (2006) Expansion of GAA trinucleotide repeats in mammals. Genomics 87:57-67
Sharma, Rajesh; De Biase, Irene; Gomez, Mariluz et al. (2004) Friedreich ataxia in carriers of unstable borderline GAA triplet-repeat alleles. Ann Neurol 56:898-901

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