ETHE1 mutations are specific to ethylmalonic encephalopathy

V. Tiranti, E. Briem, E. Lamantea, R. Mineri, E. Papaleo, L. De Gioia, F. Forlani, P. Rinaldo, P. Dickson, B. Abu-Libdeh, L. Cindro-Heberle, M. Owaidha, R. M. Jack, E. Christensen, A. Burlina, M. Zeviani

Research output: Contribution to journalArticle

Abstract

Mutations in ETHE1, a gene located at chromosome 19q13, have recently been identified in patients affected by ethylmalonic encephalopathy (EE). EE is a devastating infantile metabolic disorder, characterised by widespread lesions in the brain, hyperlactic acidaemia, petechiae, orthostatic acrocyanosis, and high levels of ethylmalonic acid in body fluids. To investigate to what extent ETHE1 is responsible for EE, we analysed this gene in 29 patients with typical EE and in 11 patients presenting with early onset progressive encephalopathy with ethylmalonic aciduria (non-EE EMA). Frameshift, stop, splice site, and missense mutations of ETHE1 were detected in all the typical EE patients analysed. Western blot analysis of the ETHE1 protein indicated that some of the missense mutations are associated with the presence of the protein, suggesting that the corresponding wild type amino acid residues have a catalytic function. No ETHE1 mutations were identified in non-EE EMA patients. Experiments based on two dimensional blue native electrophoresis indicated that ETHE1 protein works as a supramolecular, presumably homodimeric, complex, and a three dimensional model of the protein suggests that it is likely to be a mitochondrial matrix thioesterase acting on a still unknown substrate. Finally, the 625G→A single nucleotide polymorphism in the gene encoding the short chain acyl-coenzyme A dehydrogenase (SCAD) was previously proposed as a co-factor in the aetiology of EE and other EMA syndromes. SNP analysis in our patients ruled out a pathogenic role of SCAD variants in EE, but did show a highly significant prevalence of the 625A alleles in non-EE EMA patients.

Original languageEnglish
Pages (from-to)340-346
Number of pages7
JournalJournal of Medical Genetics
Volume43
Issue number4
DOIs
Publication statusPublished - Apr 2006

Fingerprint

Mutation
Brain Diseases
Acyl-CoA Dehydrogenase
Missense Mutation
Single Nucleotide Polymorphism
Proteins
Genes
Purpura
Ethylmalonic encephalopathy
Body Fluids
Electrophoresis
Chromosomes
Western Blotting
Alleles
Amino Acids
Brain

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

ETHE1 mutations are specific to ethylmalonic encephalopathy. / Tiranti, V.; Briem, E.; Lamantea, E.; Mineri, R.; Papaleo, E.; De Gioia, L.; Forlani, F.; Rinaldo, P.; Dickson, P.; Abu-Libdeh, B.; Cindro-Heberle, L.; Owaidha, M.; Jack, R. M.; Christensen, E.; Burlina, A.; Zeviani, M.

In: Journal of Medical Genetics, Vol. 43, No. 4, 04.2006, p. 340-346.

Research output: Contribution to journalArticle

Tiranti, V, Briem, E, Lamantea, E, Mineri, R, Papaleo, E, De Gioia, L, Forlani, F, Rinaldo, P, Dickson, P, Abu-Libdeh, B, Cindro-Heberle, L, Owaidha, M, Jack, RM, Christensen, E, Burlina, A & Zeviani, M 2006, 'ETHE1 mutations are specific to ethylmalonic encephalopathy', Journal of Medical Genetics, vol. 43, no. 4, pp. 340-346. https://doi.org/10.1136/jmg.2005.036210
Tiranti, V. ; Briem, E. ; Lamantea, E. ; Mineri, R. ; Papaleo, E. ; De Gioia, L. ; Forlani, F. ; Rinaldo, P. ; Dickson, P. ; Abu-Libdeh, B. ; Cindro-Heberle, L. ; Owaidha, M. ; Jack, R. M. ; Christensen, E. ; Burlina, A. ; Zeviani, M. / ETHE1 mutations are specific to ethylmalonic encephalopathy. In: Journal of Medical Genetics. 2006 ; Vol. 43, No. 4. pp. 340-346.
@article{4cd081f21a8f49ac939c267d42914c89,
title = "ETHE1 mutations are specific to ethylmalonic encephalopathy",
abstract = "Mutations in ETHE1, a gene located at chromosome 19q13, have recently been identified in patients affected by ethylmalonic encephalopathy (EE). EE is a devastating infantile metabolic disorder, characterised by widespread lesions in the brain, hyperlactic acidaemia, petechiae, orthostatic acrocyanosis, and high levels of ethylmalonic acid in body fluids. To investigate to what extent ETHE1 is responsible for EE, we analysed this gene in 29 patients with typical EE and in 11 patients presenting with early onset progressive encephalopathy with ethylmalonic aciduria (non-EE EMA). Frameshift, stop, splice site, and missense mutations of ETHE1 were detected in all the typical EE patients analysed. Western blot analysis of the ETHE1 protein indicated that some of the missense mutations are associated with the presence of the protein, suggesting that the corresponding wild type amino acid residues have a catalytic function. No ETHE1 mutations were identified in non-EE EMA patients. Experiments based on two dimensional blue native electrophoresis indicated that ETHE1 protein works as a supramolecular, presumably homodimeric, complex, and a three dimensional model of the protein suggests that it is likely to be a mitochondrial matrix thioesterase acting on a still unknown substrate. Finally, the 625G→A single nucleotide polymorphism in the gene encoding the short chain acyl-coenzyme A dehydrogenase (SCAD) was previously proposed as a co-factor in the aetiology of EE and other EMA syndromes. SNP analysis in our patients ruled out a pathogenic role of SCAD variants in EE, but did show a highly significant prevalence of the 625A alleles in non-EE EMA patients.",
author = "V. Tiranti and E. Briem and E. Lamantea and R. Mineri and E. Papaleo and {De Gioia}, L. and F. Forlani and P. Rinaldo and P. Dickson and B. Abu-Libdeh and L. Cindro-Heberle and M. Owaidha and Jack, {R. M.} and E. Christensen and A. Burlina and M. Zeviani",
year = "2006",
month = "4",
doi = "10.1136/jmg.2005.036210",
language = "English",
volume = "43",
pages = "340--346",
journal = "Journal of Medical Genetics",
issn = "0022-2593",
publisher = "BMJ Publishing Group",
number = "4",

}

TY - JOUR

T1 - ETHE1 mutations are specific to ethylmalonic encephalopathy

AU - Tiranti, V.

AU - Briem, E.

AU - Lamantea, E.

AU - Mineri, R.

AU - Papaleo, E.

AU - De Gioia, L.

AU - Forlani, F.

AU - Rinaldo, P.

AU - Dickson, P.

AU - Abu-Libdeh, B.

AU - Cindro-Heberle, L.

AU - Owaidha, M.

AU - Jack, R. M.

AU - Christensen, E.

AU - Burlina, A.

AU - Zeviani, M.

PY - 2006/4

Y1 - 2006/4

N2 - Mutations in ETHE1, a gene located at chromosome 19q13, have recently been identified in patients affected by ethylmalonic encephalopathy (EE). EE is a devastating infantile metabolic disorder, characterised by widespread lesions in the brain, hyperlactic acidaemia, petechiae, orthostatic acrocyanosis, and high levels of ethylmalonic acid in body fluids. To investigate to what extent ETHE1 is responsible for EE, we analysed this gene in 29 patients with typical EE and in 11 patients presenting with early onset progressive encephalopathy with ethylmalonic aciduria (non-EE EMA). Frameshift, stop, splice site, and missense mutations of ETHE1 were detected in all the typical EE patients analysed. Western blot analysis of the ETHE1 protein indicated that some of the missense mutations are associated with the presence of the protein, suggesting that the corresponding wild type amino acid residues have a catalytic function. No ETHE1 mutations were identified in non-EE EMA patients. Experiments based on two dimensional blue native electrophoresis indicated that ETHE1 protein works as a supramolecular, presumably homodimeric, complex, and a three dimensional model of the protein suggests that it is likely to be a mitochondrial matrix thioesterase acting on a still unknown substrate. Finally, the 625G→A single nucleotide polymorphism in the gene encoding the short chain acyl-coenzyme A dehydrogenase (SCAD) was previously proposed as a co-factor in the aetiology of EE and other EMA syndromes. SNP analysis in our patients ruled out a pathogenic role of SCAD variants in EE, but did show a highly significant prevalence of the 625A alleles in non-EE EMA patients.

AB - Mutations in ETHE1, a gene located at chromosome 19q13, have recently been identified in patients affected by ethylmalonic encephalopathy (EE). EE is a devastating infantile metabolic disorder, characterised by widespread lesions in the brain, hyperlactic acidaemia, petechiae, orthostatic acrocyanosis, and high levels of ethylmalonic acid in body fluids. To investigate to what extent ETHE1 is responsible for EE, we analysed this gene in 29 patients with typical EE and in 11 patients presenting with early onset progressive encephalopathy with ethylmalonic aciduria (non-EE EMA). Frameshift, stop, splice site, and missense mutations of ETHE1 were detected in all the typical EE patients analysed. Western blot analysis of the ETHE1 protein indicated that some of the missense mutations are associated with the presence of the protein, suggesting that the corresponding wild type amino acid residues have a catalytic function. No ETHE1 mutations were identified in non-EE EMA patients. Experiments based on two dimensional blue native electrophoresis indicated that ETHE1 protein works as a supramolecular, presumably homodimeric, complex, and a three dimensional model of the protein suggests that it is likely to be a mitochondrial matrix thioesterase acting on a still unknown substrate. Finally, the 625G→A single nucleotide polymorphism in the gene encoding the short chain acyl-coenzyme A dehydrogenase (SCAD) was previously proposed as a co-factor in the aetiology of EE and other EMA syndromes. SNP analysis in our patients ruled out a pathogenic role of SCAD variants in EE, but did show a highly significant prevalence of the 625A alleles in non-EE EMA patients.

UR - http://www.scopus.com/inward/record.url?scp=33645758448&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33645758448&partnerID=8YFLogxK

U2 - 10.1136/jmg.2005.036210

DO - 10.1136/jmg.2005.036210

M3 - Article

C2 - 16183799

AN - SCOPUS:33645758448

VL - 43

SP - 340

EP - 346

JO - Journal of Medical Genetics

JF - Journal of Medical Genetics

SN - 0022-2593

IS - 4

ER -