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Missense mutations linked to friedreich ataxia have different but synergistic effects on mitochondrial frataxin isoforms.

ABSTRACT: Friedreich ataxia is an early-onset multisystemic disease linked to a variety of molecular defects in the nuclear gene FRDA. This gene normally encodes the iron-binding protein frataxin (FXN), which is critical for mitochondrial iron metabolism, global cellular iron homeostasis, and antioxidant protection. In most Friedreich ataxia patients, a large GAA-repeat expansion is present within the first intron of both FRDA alleles, that results in transcriptional silencing ultimately leading to insufficient levels of FXN protein in the mitochondrial matrix and probably other cellular compartments. The lack of FXN in turn impairs incorporation of iron into iron-sulfur cluster and heme cofactors, causing widespread enzymatic deficits and oxidative damage catalyzed by excess labile iron. In a minority of patients, a typical GAA expansion is present in only one FRDA allele, whereas a missense mutation is found in the other allele. Although it is known that the disease course for these patients can be as severe as for patients with two expanded FRDA alleles, the underlying pathophysiological mechanisms are not understood. Human cells normally contain two major mitochondrial isoforms of FXN (FXN(42-210) and FXN(81-210)) that have different biochemical properties and functional roles. Using cell-free systems and different cellular models, we show that two of the most clinically severe FXN point mutations, I154F and W155R, have unique direct and indirect effects on the stability, biogenesis, or catalytic activity of FXN(42-210) and FXN(81-210) under physiological conditions. Our data indicate that frataxin point mutations have complex biochemical effects that synergistically contribute to the pathophysiology of Friedreich ataxia.

SUBMITTER: Li H

PROVIDER: S-EPMC3567662 | biostudies-literature | 2013 Feb

REPOSITORIES: biostudies-literature

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Missense mutations linked to friedreich ataxia have different but synergistic effects on mitochondrial frataxin isoforms.

Li Hongqiao H Gakh Oleksandr O Smith Douglas Y DY Ranatunga Wasantha K WK Isaya Grazia G

The Journal of biological chemistry 20121226 6

Friedreich ataxia is an early-onset multisystemic disease linked to a variety of molecular defects in the nuclear gene FRDA. This gene normally encodes the iron-binding protein frataxin (FXN), which is critical for mitochondrial iron metabolism, global cellular iron homeostasis, and antioxidant protection. In most Friedreich ataxia patients, a large GAA-repeat expansion is present within the first intron of both FRDA alleles, that results in transcriptional silencing ultimately leading to insuff ...[more]

PMID: 23269675

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Project description:BACKGROUND: Friedreich ataxia, an autosomal recessive neurodegenerative and cardiac disease, is caused by abnormally low levels of frataxin, an essential mitochondrial protein. All Friedreich ataxia patients carry a GAATTC repeat expansion in the first intron of the frataxin gene, either in the homozygous state or in compound heterozygosity with other loss-of-function mutations. The GAA expansion inhibits frataxin expression through a heterochromatin-mediated repression mechanism. Histone modifications that are characteristic of silenced genes in heterochromatic regions occur at expanded alleles in cells from Friedreich ataxia patients, including increased trimethylation of histone H3 at lysine 9 and hypoacetylation of histones H3 and H4. METHODOLOGY/PRINCIPAL FINDINGS: By chromatin immunoprecipitation, we detected the same heterochromatin marks in homozygous mice carrying a (GAA)(230) repeat in the first intron of the mouse frataxin gene (KIKI mice). These animals have decreased frataxin levels and, by microarray analysis, show significant gene expression changes in several tissues. We treated KIKI mice with a novel histone deacetylase inhibitor, compound 106, which substantially increases frataxin mRNA levels in cells from Friedreich ataxia individuals. Treatment increased histone H3 and H4 acetylation in chromatin near the GAA repeat and restored wild-type frataxin levels in the nervous system and heart, as determined by quantitative RT-PCR and semiquantitative western blot analysis. No toxicity was observed. Furthermore, most of the differentially expressed genes in KIKI mice reverted towards wild-type levels. CONCLUSIONS/SIGNIFICANCE: Lack of acute toxicity, normalization of frataxin levels and of the transcription profile changes resulting from frataxin deficiency provide strong support to a possible efficacy of this or related compounds in reverting the pathological process in Friedreich ataxia, a so far incurable neurodegenerative disease.

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Missense mutations linked to friedreich ataxia have different but synergistic effects on mitochondrial frataxin isoforms.

Publications

Missense mutations linked to friedreich ataxia have different but synergistic effects on mitochondrial frataxin isoforms.

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