J.L. Bradley1, J.C. Blake1, S. Chamberlain2, P.K. Thomas1,3, J.M. Cooper1 and ..... Clark, J.B. (1990) Mitochondrial myopathy with a defect of mitochondrial.
© 2000 Oxford University Press
Human Molecular Genetics, 2000, Vol. 9, No. 2
275–282
Clinical, biochemical and molecular genetic correlations in Friedreich’s ataxia J.L. Bradley1, J.C. Blake1, S. Chamberlain2, P.K. Thomas1,3, J.M. Cooper1 and A.H.V. Schapira1,3,+ 1University
Department of Clinical Neurosciences, Royal Free and University College Medical School, London, UK, of Human Genetics, Imperial College of Medicine at St Mary’s, London, UK and 3Institute of Neurology, University College London, London, UK 2Department
Received 17 September 1999; Revised and Accepted 17 November 1999
Friedreich’s ataxia (FRDA) is an autosomal recessive disorder with a frequency of 1 in 50 000 live births. In 97% of patients it is caused by the abnormal expansion of a GAA repeat in intron 1 of the FRDA gene on chromosome 9, which encodes a 210 amino acid protein called frataxin. Frataxin is widely expressed and has been localized to mitochondria although its function is unknown. We have investigated mitochondrial function, mitochondrial DNA levels, aconitase activity and iron content in tissues from FRDA patients. There were significant reductions in the activities of complex I, complex II/III and aconitase in FRDA heart. Respiratory chain and aconitase activities were decreased although not significantly in skeletal muscle, but were normal in FRDA cerebellum and dorsal root ganglia, although there was a mild decrease in aconitase activity in the latter. Mitochondrial DNA levels were reduced in FRDA heart and skeletal muscle, although in skeletal muscle this was paralleled by a decline in citrate synthase activity. Increased iron deposition was seen in FRDA heart, liver and spleen in a pattern consistent with a mitochondrial location. The iron accumulation, mitochondrial respiratory chain and aconitase dysfunction and mitochondrial DNA depletion in FRDA heart samples largely paralleled those in the yeast YFH1 knockout model, suggesting that frataxin may be involved in mitochondrial iron regulation or iron sulphur centre synthesis. However, the severe deficiency in aconitase activity also suggests that oxidant stress may induce a self-amplifying cycle of oxidative damage and mitochondrial dysfunction, which may contribute to cellular toxicity. INTRODUCTION FRDA is characterized clinically by onset usually below the age of 20 years of progressive ataxia, tendon areflexia, lower limb weakness and large fibre sensory loss. A significant proportion of
patients develop cardiomyopathy (a frequent eventual cause of death), diabetes mellitus and skeletal abnormalities such as kyphoscoliosis. The chromosomal locus for FRDA (9q13) was reported in 1988 (1), and the responsible gene (FRDA) in 1996 (2), which encodes frataxin, a widely expressed protein which has a mitochondrial targeting sequence and has been shown to colocalize to mitochondria (3). In 97% of FRDA patients there is an increase (>200) in the number of GAA repeats in intron 1, over and above those seen in controls (
