Frataxin levels in peripheral tissue in Friedreich ataxia.
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.


CONCLUSIONS
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.
Departments of Pediatrics and Neurology, Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania Philadelphia, Pennsylvania, 19104.
Michael
M
Lazaropoulos
Departments of Pediatrics and Neurology, Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania Philadelphia, Pennsylvania, 19104.
Yina
Y
Dong
Departments of Pediatrics and Neurology, Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania Philadelphia, Pennsylvania, 19104.
Elisia
E
Clark
Departments of Pediatrics and Neurology, Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania Philadelphia, Pennsylvania, 19104.
Nathaniel R
NR
Greeley
Departments of Pediatrics and Neurology, Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania Philadelphia, Pennsylvania, 19104.
Lauren A
LA
Seyer
Departments of Pediatrics and Neurology, Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania Philadelphia, Pennsylvania, 19104.
Karlla W
KW
Brigatti
Departments of Pediatrics and Neurology, Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania Philadelphia, Pennsylvania, 19104.
Carlton
C
Christie
Department of Neurology, University of California Los Angeles Los Angeles, California.
Susan L
SL
Perlman
Department of Neurology, Emory University Atlanta, Georgia.
George R
GR
Wilmot
Department of Neurology, University of Chicago Chicago, Illinois.
Christoper M
CM
Gomez
Department of Neurology, University of Iowa Iowa City, Iowa.
Katherine D
KD
Mathews
Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, University of Toronto Toronto, Ontario, Canada.
Grace
G
Yoon
Department of Neurology, University of South Florida Tampa, Florida.
Theresa
T
Zesiewicz
Department of Neurology, The Ohio State University Columbus, Ohio.
Chad
C
Hoyle
Department of Neurology, University of Florida Gainesville, Florida.
Sub H
SH
Subramony
Department of Neurology, University of Rochester Rochester, New York.
Alicia F
AF
Brocht
Departments of Pediatrics and Neurology, Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania Philadelphia, Pennsylvania, 19104.
Jennifer M
JM
Farmer
Department of Pathology and Lab Medicine, Perelman School of Medicine, University of Pennsylvania Philadelphia, Pennsylvania, 19104.
Robert B
RB
Wilson
Departments of Pediatrics and Neurology, Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania Philadelphia, Pennsylvania, 19104.
Eric C
EC
Deutsch
Departments of Pediatrics and Neurology, Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania Philadelphia, Pennsylvania, 19104.
David R
DR
Lynch