Reduced levels of frataxin, an essential mitochondrial protein involved in the regulation of iron-sulfur cluster biogenesis, are responsible for the recessive neurodegenerative Friedreich Ataxia (FRDA). Expansion of a GAA triplet in the first intron of the FRDA is essential tor disease development which causes partial silencing of frataxin. In the vast majority of cases, patients are homozygotes for the expansion, but a small number of FRDA patients are heterozygotes for expansion and point mutations in the frataxin coding frame. In this study, we analyze the effects of a point mutation G137V. The patient P94-2, with a history of alcohol and drug abuse, showed a FRDA onset at the border between the classic and late onset phenotype. We applied a combination of biophysical and biochemical methods to characterize its effects on the structure, folding and activity of frataxin. Our study reveals no impairment of the structure or activity of the protein but a reduced folding stability. We suggest that the mutation causes misfolding of the native chain with consequent reduction of the protein concentration in the patient and discuss the possible mechanism of disease.

Faggianelli, N., Puglisi, R., Veneziano, L., Romano, S., Frontali, M., Vannocci, T., et al. (2015). Analyzing the effects of a G137V mutation in the FXN gene. FRONTIERS IN MOLECULAR NEUROSCIENCE, 8 [10.3389/fnmol.2015.00066].

Analyzing the effects of a G137V mutation in the FXN gene

Fortuni, S;Testi, R;
2015-01-01

Abstract

Reduced levels of frataxin, an essential mitochondrial protein involved in the regulation of iron-sulfur cluster biogenesis, are responsible for the recessive neurodegenerative Friedreich Ataxia (FRDA). Expansion of a GAA triplet in the first intron of the FRDA is essential tor disease development which causes partial silencing of frataxin. In the vast majority of cases, patients are homozygotes for the expansion, but a small number of FRDA patients are heterozygotes for expansion and point mutations in the frataxin coding frame. In this study, we analyze the effects of a point mutation G137V. The patient P94-2, with a history of alcohol and drug abuse, showed a FRDA onset at the border between the classic and late onset phenotype. We applied a combination of biophysical and biochemical methods to characterize its effects on the structure, folding and activity of frataxin. Our study reveals no impairment of the structure or activity of the protein but a reduced folding stability. We suggest that the mutation causes misfolding of the native chain with consequent reduction of the protein concentration in the patient and discuss the possible mechanism of disease.
2015
Pubblicato
Rilevanza internazionale
Articolo
Esperti anonimi
Settore MED/04 - PATOLOGIA GENERALE
English
Disease mechanisms; Frataxin; Friedreich’s ataxia; Functional mutants; Protein folding;
disease mechanisms; frataxin; friedreich's ataxia; functional mutants; protein folding
Faggianelli, N., Puglisi, R., Veneziano, L., Romano, S., Frontali, M., Vannocci, T., et al. (2015). Analyzing the effects of a G137V mutation in the FXN gene. FRONTIERS IN MOLECULAR NEUROSCIENCE, 8 [10.3389/fnmol.2015.00066].
Faggianelli, N; Puglisi, R; Veneziano, L; Romano, S; Frontali, M; Vannocci, T; Fortuni, S; Testi, R; Pastore, A
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2108/217280
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