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Frataxin levels in peripheral tissue in Friedreich ataxia.

Lazaropoulos M, Dong Y, Clark E, Greeley NR, Seyer LA, Brigatti KW, Christie C, Perlman SL, Wilmot GR, Gomez CM, Mathews KD, Yoon G, Zesiewicz T, Hoyle C, Subramony SH, Brocht AF, Farmer JM, Wilson RB, Deutsch EC, Lynch DR - Ann Clin Transl Neurol (2015)

Bottom Line: Such mutations, usually expanded guanine-adenine-adenine (GAA) repeats, give rise to decreased levels of frataxin protein in both affected and unaffected tissues.Site-directed mutant frataxin was also transfected into human embryonic kidney cells to model results from specific point mutations.The G130V mutation led to decreased levels of frataxin in vitro as well as in vivo, while the R165C mutation produced normal immunoreactive levels of frataxin both in vitro and in vivo.

View Article: PubMed Central - PubMed

Affiliation: Departments of Pediatrics and Neurology, Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania Philadelphia, Pennsylvania, 19104.

ABSTRACT

Objective: Friedreich ataxia (FRDA) is an autosomal recessive ataxia resulting from mutations in the frataxin gene (FXN). Such mutations, usually expanded guanine-adenine-adenine (GAA) repeats, give rise to decreased levels of frataxin protein in both affected and unaffected tissues. The goal was to understand the relationship of frataxin levels in peripheral tissues to disease status.

Methods: Frataxin levels were measured in buccal cells and blood, and analyzed in relation to disease features. Site-directed mutant frataxin was also transfected into human embryonic kidney cells to model results from specific point mutations.

Results: There was no evidence for change in frataxin levels over time with repeated measures analysis, although linear regression analysis of cross-sectional data predicted a small increase over decades. GAA repeat length predicted frataxin levels in both tissues, and frataxin levels themselves predicted neurological ratings (accounting for age). Compound heterozygous patients for a GAA expansion and a point mutation in FXN generally had lower levels of frataxin than those homozygous for the presence of two GAA repeat expansions, though levels varied dramatically between tissues in some compound heterozygotes for point mutations. The G130V mutation led to decreased levels of frataxin in vitro as well as in vivo, while the R165C mutation produced normal immunoreactive levels of frataxin both in vitro and in vivo. Start codon mutations led to low levels of frataxin in buccal cells but preserved immunoreactive frataxin levels in blood.

Interpretation: The present data show that peripheral frataxin levels reflect disease features in FRDA, but emphasize the need for interpretation of such levels in the context of specific mutations.

No MeSH data available.


Related in: MedlinePlus

Relationship between ratio of buccal to whole blood frataxin levels and disease features. The ratio of buccal to blood frataxin level (ordinate) correlates with the short guanine–adenine–adenine (GAA) length (abscissa) (P < 0.001). Longer GAA repeats are associated with a high buccal/blood ratio. N = 230 for ratio.
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fig03: Relationship between ratio of buccal to whole blood frataxin levels and disease features. The ratio of buccal to blood frataxin level (ordinate) correlates with the short guanine–adenine–adenine (GAA) length (abscissa) (P < 0.001). Longer GAA repeats are associated with a high buccal/blood ratio. N = 230 for ratio.

Mentions: The GAA repeat in FRDA may display somatic variability that mediates the tissue selectivity of FRDA23; thus the ratio of buccal and whole blood frataxin measurements was also analyzed. While the mean ratio was 1.00, the buccal to blood ratio correlated with the repeat length of the shorter allele (R2 = 0.0703, P < 0.001) and the age at collection (R2 = 0.0173, P = 0.034) (Fig.3). But only GAA repeat length predicted the ratio in multivariate models (regression coefficient = 0.00082 ± 0.00027; P = 0.003; R2 = 0.073).


Frataxin levels in peripheral tissue in Friedreich ataxia.

Lazaropoulos M, Dong Y, Clark E, Greeley NR, Seyer LA, Brigatti KW, Christie C, Perlman SL, Wilmot GR, Gomez CM, Mathews KD, Yoon G, Zesiewicz T, Hoyle C, Subramony SH, Brocht AF, Farmer JM, Wilson RB, Deutsch EC, Lynch DR - Ann Clin Transl Neurol (2015)

Relationship between ratio of buccal to whole blood frataxin levels and disease features. The ratio of buccal to blood frataxin level (ordinate) correlates with the short guanine–adenine–adenine (GAA) length (abscissa) (P < 0.001). Longer GAA repeats are associated with a high buccal/blood ratio. N = 230 for ratio.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4554444&req=5

fig03: Relationship between ratio of buccal to whole blood frataxin levels and disease features. The ratio of buccal to blood frataxin level (ordinate) correlates with the short guanine–adenine–adenine (GAA) length (abscissa) (P < 0.001). Longer GAA repeats are associated with a high buccal/blood ratio. N = 230 for ratio.
Mentions: The GAA repeat in FRDA may display somatic variability that mediates the tissue selectivity of FRDA23; thus the ratio of buccal and whole blood frataxin measurements was also analyzed. While the mean ratio was 1.00, the buccal to blood ratio correlated with the repeat length of the shorter allele (R2 = 0.0703, P < 0.001) and the age at collection (R2 = 0.0173, P = 0.034) (Fig.3). But only GAA repeat length predicted the ratio in multivariate models (regression coefficient = 0.00082 ± 0.00027; P = 0.003; R2 = 0.073).

Bottom Line: Such mutations, usually expanded guanine-adenine-adenine (GAA) repeats, give rise to decreased levels of frataxin protein in both affected and unaffected tissues.Site-directed mutant frataxin was also transfected into human embryonic kidney cells to model results from specific point mutations.The G130V mutation led to decreased levels of frataxin in vitro as well as in vivo, while the R165C mutation produced normal immunoreactive levels of frataxin both in vitro and in vivo.

View Article: PubMed Central - PubMed

Affiliation: Departments of Pediatrics and Neurology, Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania Philadelphia, Pennsylvania, 19104.

ABSTRACT

Objective: Friedreich ataxia (FRDA) is an autosomal recessive ataxia resulting from mutations in the frataxin gene (FXN). Such mutations, usually expanded guanine-adenine-adenine (GAA) repeats, give rise to decreased levels of frataxin protein in both affected and unaffected tissues. The goal was to understand the relationship of frataxin levels in peripheral tissues to disease status.

Methods: Frataxin levels were measured in buccal cells and blood, and analyzed in relation to disease features. Site-directed mutant frataxin was also transfected into human embryonic kidney cells to model results from specific point mutations.

Results: There was no evidence for change in frataxin levels over time with repeated measures analysis, although linear regression analysis of cross-sectional data predicted a small increase over decades. GAA repeat length predicted frataxin levels in both tissues, and frataxin levels themselves predicted neurological ratings (accounting for age). Compound heterozygous patients for a GAA expansion and a point mutation in FXN generally had lower levels of frataxin than those homozygous for the presence of two GAA repeat expansions, though levels varied dramatically between tissues in some compound heterozygotes for point mutations. The G130V mutation led to decreased levels of frataxin in vitro as well as in vivo, while the R165C mutation produced normal immunoreactive levels of frataxin both in vitro and in vivo. Start codon mutations led to low levels of frataxin in buccal cells but preserved immunoreactive frataxin levels in blood.

Interpretation: The present data show that peripheral frataxin levels reflect disease features in FRDA, but emphasize the need for interpretation of such levels in the context of specific mutations.

No MeSH data available.


Related in: MedlinePlus