Infantile encephalopathy and defective mitochondrial DNA translation in patients with mutations of mitochondrial elongation factors EFG1 and EFTu

Lucia Valente, Valeria Tiranti, René Massimiliano Marsano, Edoardo Malfatti, Erika Fernandez-Vizarra, Claudia Donnini, Paolo Mereghetti, Luca De Gioia, Alberto Burlina, Claudio Castellan, Giacomo P. Comi, Salvatore Savasta, Iliana Ferrero, Massimo Zeviani

Research output: Contribution to journalArticle

Abstract

Mitochondrial protein translation is a complex process performed within mitochondria by an apparatus composed of mitochondrial DNA (mtDNA)-encoded RNAs and nuclear DNA-encoded proteins. Although the latter by far outnumber the former, the vast majority of mitochondrial translation defects in humans have been associated with mutations in RNA-encoding mtDNA genes, whereas mutations in protein-encoding nuclear genes have been identified in a handful of cases. Genetic investigation involving patients with defective mitochondrial translation led us to the discovery of novel mutations in the mitochondrial elongation factor G1 (EFG1) in one affected baby and, for the first time, in the mitochondrial elongation factor Tu (EFTu) in another one. Both patients were affected by severe lactic acidosis and rapidly progressive, fatal encephalopathy. The EFG1-mutant patient had early-onset Leigh syndrome, whereas the EFTu-mutant patient had severe infantile macrocystic leukodystrophy with micropolygyria. Structural modeling enabled us to make predictions about the effects of the mutations at the molecular level. Yeast and mammalian cell systems proved the pathogenic role of the mutant alleles by functional complementation in vivo. Nuclear-gene abnormalities causing mitochondrial translation defects represent a new, potentially broad field of mitochondrial medicine. Investigation of these defects is important to expand the molecular characterization of mitochondrial disorders and also may contribute to the elucidation of the complex control mechanisms, which regulate this fundamental pathway of mtDNA homeostasis.

Original languageEnglish
Pages (from-to)44-58
Number of pages15
JournalAmerican Journal of Human Genetics
Volume80
Issue number1
DOIs
Publication statusPublished - Jan 2007

Fingerprint

Peptide Elongation Factor Tu
Peptide Elongation Factors
Brain Diseases
Mitochondrial DNA
Mutation
Leigh Disease
Nuclear RNA
Mitochondrial Diseases
Lactic Acidosis
Mitochondrial Genes
Mitochondrial Proteins
Protein Biosynthesis
Nuclear Proteins
Genes
Mitochondria
Homeostasis
Yeasts
Alleles
Medicine
RNA

ASJC Scopus subject areas

  • Genetics

Cite this

Infantile encephalopathy and defective mitochondrial DNA translation in patients with mutations of mitochondrial elongation factors EFG1 and EFTu. / Valente, Lucia; Tiranti, Valeria; Marsano, René Massimiliano; Malfatti, Edoardo; Fernandez-Vizarra, Erika; Donnini, Claudia; Mereghetti, Paolo; De Gioia, Luca; Burlina, Alberto; Castellan, Claudio; Comi, Giacomo P.; Savasta, Salvatore; Ferrero, Iliana; Zeviani, Massimo.

In: American Journal of Human Genetics, Vol. 80, No. 1, 01.2007, p. 44-58.

Research output: Contribution to journalArticle

Valente, L, Tiranti, V, Marsano, RM, Malfatti, E, Fernandez-Vizarra, E, Donnini, C, Mereghetti, P, De Gioia, L, Burlina, A, Castellan, C, Comi, GP, Savasta, S, Ferrero, I & Zeviani, M 2007, 'Infantile encephalopathy and defective mitochondrial DNA translation in patients with mutations of mitochondrial elongation factors EFG1 and EFTu', American Journal of Human Genetics, vol. 80, no. 1, pp. 44-58. https://doi.org/10.1086/510559
Valente, Lucia ; Tiranti, Valeria ; Marsano, René Massimiliano ; Malfatti, Edoardo ; Fernandez-Vizarra, Erika ; Donnini, Claudia ; Mereghetti, Paolo ; De Gioia, Luca ; Burlina, Alberto ; Castellan, Claudio ; Comi, Giacomo P. ; Savasta, Salvatore ; Ferrero, Iliana ; Zeviani, Massimo. / Infantile encephalopathy and defective mitochondrial DNA translation in patients with mutations of mitochondrial elongation factors EFG1 and EFTu. In: American Journal of Human Genetics. 2007 ; Vol. 80, No. 1. pp. 44-58.
@article{117e9b2b983a480b9a9d7454041a93de,
title = "Infantile encephalopathy and defective mitochondrial DNA translation in patients with mutations of mitochondrial elongation factors EFG1 and EFTu",
abstract = "Mitochondrial protein translation is a complex process performed within mitochondria by an apparatus composed of mitochondrial DNA (mtDNA)-encoded RNAs and nuclear DNA-encoded proteins. Although the latter by far outnumber the former, the vast majority of mitochondrial translation defects in humans have been associated with mutations in RNA-encoding mtDNA genes, whereas mutations in protein-encoding nuclear genes have been identified in a handful of cases. Genetic investigation involving patients with defective mitochondrial translation led us to the discovery of novel mutations in the mitochondrial elongation factor G1 (EFG1) in one affected baby and, for the first time, in the mitochondrial elongation factor Tu (EFTu) in another one. Both patients were affected by severe lactic acidosis and rapidly progressive, fatal encephalopathy. The EFG1-mutant patient had early-onset Leigh syndrome, whereas the EFTu-mutant patient had severe infantile macrocystic leukodystrophy with micropolygyria. Structural modeling enabled us to make predictions about the effects of the mutations at the molecular level. Yeast and mammalian cell systems proved the pathogenic role of the mutant alleles by functional complementation in vivo. Nuclear-gene abnormalities causing mitochondrial translation defects represent a new, potentially broad field of mitochondrial medicine. Investigation of these defects is important to expand the molecular characterization of mitochondrial disorders and also may contribute to the elucidation of the complex control mechanisms, which regulate this fundamental pathway of mtDNA homeostasis.",
author = "Lucia Valente and Valeria Tiranti and Marsano, {Ren{\'e} Massimiliano} and Edoardo Malfatti and Erika Fernandez-Vizarra and Claudia Donnini and Paolo Mereghetti and {De Gioia}, Luca and Alberto Burlina and Claudio Castellan and Comi, {Giacomo P.} and Salvatore Savasta and Iliana Ferrero and Massimo Zeviani",
year = "2007",
month = "1",
doi = "10.1086/510559",
language = "English",
volume = "80",
pages = "44--58",
journal = "American Journal of Human Genetics",
issn = "0002-9297",
publisher = "Cell Press",
number = "1",

}

TY - JOUR

T1 - Infantile encephalopathy and defective mitochondrial DNA translation in patients with mutations of mitochondrial elongation factors EFG1 and EFTu

AU - Valente, Lucia

AU - Tiranti, Valeria

AU - Marsano, René Massimiliano

AU - Malfatti, Edoardo

AU - Fernandez-Vizarra, Erika

AU - Donnini, Claudia

AU - Mereghetti, Paolo

AU - De Gioia, Luca

AU - Burlina, Alberto

AU - Castellan, Claudio

AU - Comi, Giacomo P.

AU - Savasta, Salvatore

AU - Ferrero, Iliana

AU - Zeviani, Massimo

PY - 2007/1

Y1 - 2007/1

N2 - Mitochondrial protein translation is a complex process performed within mitochondria by an apparatus composed of mitochondrial DNA (mtDNA)-encoded RNAs and nuclear DNA-encoded proteins. Although the latter by far outnumber the former, the vast majority of mitochondrial translation defects in humans have been associated with mutations in RNA-encoding mtDNA genes, whereas mutations in protein-encoding nuclear genes have been identified in a handful of cases. Genetic investigation involving patients with defective mitochondrial translation led us to the discovery of novel mutations in the mitochondrial elongation factor G1 (EFG1) in one affected baby and, for the first time, in the mitochondrial elongation factor Tu (EFTu) in another one. Both patients were affected by severe lactic acidosis and rapidly progressive, fatal encephalopathy. The EFG1-mutant patient had early-onset Leigh syndrome, whereas the EFTu-mutant patient had severe infantile macrocystic leukodystrophy with micropolygyria. Structural modeling enabled us to make predictions about the effects of the mutations at the molecular level. Yeast and mammalian cell systems proved the pathogenic role of the mutant alleles by functional complementation in vivo. Nuclear-gene abnormalities causing mitochondrial translation defects represent a new, potentially broad field of mitochondrial medicine. Investigation of these defects is important to expand the molecular characterization of mitochondrial disorders and also may contribute to the elucidation of the complex control mechanisms, which regulate this fundamental pathway of mtDNA homeostasis.

AB - Mitochondrial protein translation is a complex process performed within mitochondria by an apparatus composed of mitochondrial DNA (mtDNA)-encoded RNAs and nuclear DNA-encoded proteins. Although the latter by far outnumber the former, the vast majority of mitochondrial translation defects in humans have been associated with mutations in RNA-encoding mtDNA genes, whereas mutations in protein-encoding nuclear genes have been identified in a handful of cases. Genetic investigation involving patients with defective mitochondrial translation led us to the discovery of novel mutations in the mitochondrial elongation factor G1 (EFG1) in one affected baby and, for the first time, in the mitochondrial elongation factor Tu (EFTu) in another one. Both patients were affected by severe lactic acidosis and rapidly progressive, fatal encephalopathy. The EFG1-mutant patient had early-onset Leigh syndrome, whereas the EFTu-mutant patient had severe infantile macrocystic leukodystrophy with micropolygyria. Structural modeling enabled us to make predictions about the effects of the mutations at the molecular level. Yeast and mammalian cell systems proved the pathogenic role of the mutant alleles by functional complementation in vivo. Nuclear-gene abnormalities causing mitochondrial translation defects represent a new, potentially broad field of mitochondrial medicine. Investigation of these defects is important to expand the molecular characterization of mitochondrial disorders and also may contribute to the elucidation of the complex control mechanisms, which regulate this fundamental pathway of mtDNA homeostasis.

UR - http://www.scopus.com/inward/record.url?scp=33846006253&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33846006253&partnerID=8YFLogxK

U2 - 10.1086/510559

DO - 10.1086/510559

M3 - Article

C2 - 17160893

AN - SCOPUS:33846006253

VL - 80

SP - 44

EP - 58

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

SN - 0002-9297

IS - 1

ER -