Mutations in APOPT1, encoding a mitochondrial protein, cause cavitating leukoencephalopathy with cytochrome c oxidase deficiency

Laura Melchionda, Tobias B. Haack, Steven Hardy, Truus E M Abbink, Erika Fernandez-Vizarra, Eleonora Lamantea, Silvia Marchet, Lucia Morandi, Maurizio Moggio, Rosalba Carrozzo, Alessandra Torraco, Daria Diodato, Tim M. Strom, Thomas Meitinger, Pinar Tekturk, Zuhal Yapici, Fathiya Al-Murshedi, Rene Stevens, Richard J. Rodenburg, Costanza Lamperti & 9 others Anna Ardissone, Isabella Moroni, Graziella Uziel, Holger Prokisch, Robert W. Taylor, Enrico Bertini, Marjo S. Van Der Knaap, Daniele Ghezzi, Massimo Zeviani

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

Cytochrome c oxidase (COX) deficiency is a frequent biochemical abnormality in mitochondrial disorders, but a large fraction of cases remains genetically undetermined.Whole-exome sequencing led to the identification of APOPT1 mutations in two Italian sisters and in a third Turkish individual presenting severe COX deficiency. All three subjects presented a distinctive brain MRI pattern characterized by cavitating leukodystrophy, predominantly in the posterior region of the cerebral hemispheres. We then found APOPT1 mutations in three additional unrelated children, selected on the basis of these particular MRI features. All identified mutations predicted the synthesis of severely damaged protein variants. The clinical features of the six subjects varied widely from acute neurometabolic decompensation in late infancy to subtle neurological signs, which appeared in adolescence; all presented a chronic, long-surviving clinical course. We showed that APOPT1 is targeted to and localized within mitochondria by an N-terminal mitochondrial targeting sequence that is eventually cleaved off from the mature protein.We then showed that APOPT1 is virtually absent in fibroblasts cultured in standard conditions, but its levels increase by inhibiting the proteasome or after oxidative challenge. Mutant fibroblasts showed reduced amount of COX holocomplex and higher levels of reactive oxygen species, which both shifted toward control values by expressing a recombinant, wild-type APOPT1 cDNA. The shRNA-mediated knockdown of APOPT1 in myoblasts and fibroblasts caused dramatic decrease in cell viability. APOPT1 mutations are responsible for infantile or childhood-onset mitochondrial disease, hallmarked by the combination of profound COX deficiency with a distinctive neuroimaging presentation..

Original languageEnglish
Pages (from-to)315-325
Number of pages11
JournalAmerican Journal of Human Genetics
Volume95
Issue number3
DOIs
Publication statusPublished - 2014

Fingerprint

Cytochrome-c Oxidase Deficiency
Leukoencephalopathies
Mitochondrial Proteins
Mitochondrial Diseases
Oxidoreductases
Mutation
Fibroblasts
Exome
Myoblasts
Cerebrum
Proteasome Endopeptidase Complex
Neuroimaging
Small Interfering RNA
Siblings
Reactive Oxygen Species
Cell Survival
Mitochondria
Proteins
Complementary DNA
Brain

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Melchionda, L., Haack, T. B., Hardy, S., Abbink, T. E. M., Fernandez-Vizarra, E., Lamantea, E., ... Zeviani, M. (2014). Mutations in APOPT1, encoding a mitochondrial protein, cause cavitating leukoencephalopathy with cytochrome c oxidase deficiency. American Journal of Human Genetics, 95(3), 315-325. https://doi.org/10.1016/j.ajhg.2014.08.003

Mutations in APOPT1, encoding a mitochondrial protein, cause cavitating leukoencephalopathy with cytochrome c oxidase deficiency. / Melchionda, Laura; Haack, Tobias B.; Hardy, Steven; Abbink, Truus E M; Fernandez-Vizarra, Erika; Lamantea, Eleonora; Marchet, Silvia; Morandi, Lucia; Moggio, Maurizio; Carrozzo, Rosalba; Torraco, Alessandra; Diodato, Daria; Strom, Tim M.; Meitinger, Thomas; Tekturk, Pinar; Yapici, Zuhal; Al-Murshedi, Fathiya; Stevens, Rene; Rodenburg, Richard J.; Lamperti, Costanza; Ardissone, Anna; Moroni, Isabella; Uziel, Graziella; Prokisch, Holger; Taylor, Robert W.; Bertini, Enrico; Van Der Knaap, Marjo S.; Ghezzi, Daniele; Zeviani, Massimo.

In: American Journal of Human Genetics, Vol. 95, No. 3, 2014, p. 315-325.

Research output: Contribution to journalArticle

Melchionda, L, Haack, TB, Hardy, S, Abbink, TEM, Fernandez-Vizarra, E, Lamantea, E, Marchet, S, Morandi, L, Moggio, M, Carrozzo, R, Torraco, A, Diodato, D, Strom, TM, Meitinger, T, Tekturk, P, Yapici, Z, Al-Murshedi, F, Stevens, R, Rodenburg, RJ, Lamperti, C, Ardissone, A, Moroni, I, Uziel, G, Prokisch, H, Taylor, RW, Bertini, E, Van Der Knaap, MS, Ghezzi, D & Zeviani, M 2014, 'Mutations in APOPT1, encoding a mitochondrial protein, cause cavitating leukoencephalopathy with cytochrome c oxidase deficiency', American Journal of Human Genetics, vol. 95, no. 3, pp. 315-325. https://doi.org/10.1016/j.ajhg.2014.08.003
Melchionda, Laura ; Haack, Tobias B. ; Hardy, Steven ; Abbink, Truus E M ; Fernandez-Vizarra, Erika ; Lamantea, Eleonora ; Marchet, Silvia ; Morandi, Lucia ; Moggio, Maurizio ; Carrozzo, Rosalba ; Torraco, Alessandra ; Diodato, Daria ; Strom, Tim M. ; Meitinger, Thomas ; Tekturk, Pinar ; Yapici, Zuhal ; Al-Murshedi, Fathiya ; Stevens, Rene ; Rodenburg, Richard J. ; Lamperti, Costanza ; Ardissone, Anna ; Moroni, Isabella ; Uziel, Graziella ; Prokisch, Holger ; Taylor, Robert W. ; Bertini, Enrico ; Van Der Knaap, Marjo S. ; Ghezzi, Daniele ; Zeviani, Massimo. / Mutations in APOPT1, encoding a mitochondrial protein, cause cavitating leukoencephalopathy with cytochrome c oxidase deficiency. In: American Journal of Human Genetics. 2014 ; Vol. 95, No. 3. pp. 315-325.
@article{d88b414e608a4f0fb590407bae0075a4,
title = "Mutations in APOPT1, encoding a mitochondrial protein, cause cavitating leukoencephalopathy with cytochrome c oxidase deficiency",
abstract = "Cytochrome c oxidase (COX) deficiency is a frequent biochemical abnormality in mitochondrial disorders, but a large fraction of cases remains genetically undetermined.Whole-exome sequencing led to the identification of APOPT1 mutations in two Italian sisters and in a third Turkish individual presenting severe COX deficiency. All three subjects presented a distinctive brain MRI pattern characterized by cavitating leukodystrophy, predominantly in the posterior region of the cerebral hemispheres. We then found APOPT1 mutations in three additional unrelated children, selected on the basis of these particular MRI features. All identified mutations predicted the synthesis of severely damaged protein variants. The clinical features of the six subjects varied widely from acute neurometabolic decompensation in late infancy to subtle neurological signs, which appeared in adolescence; all presented a chronic, long-surviving clinical course. We showed that APOPT1 is targeted to and localized within mitochondria by an N-terminal mitochondrial targeting sequence that is eventually cleaved off from the mature protein.We then showed that APOPT1 is virtually absent in fibroblasts cultured in standard conditions, but its levels increase by inhibiting the proteasome or after oxidative challenge. Mutant fibroblasts showed reduced amount of COX holocomplex and higher levels of reactive oxygen species, which both shifted toward control values by expressing a recombinant, wild-type APOPT1 cDNA. The shRNA-mediated knockdown of APOPT1 in myoblasts and fibroblasts caused dramatic decrease in cell viability. APOPT1 mutations are responsible for infantile or childhood-onset mitochondrial disease, hallmarked by the combination of profound COX deficiency with a distinctive neuroimaging presentation..",
author = "Laura Melchionda and Haack, {Tobias B.} and Steven Hardy and Abbink, {Truus E M} and Erika Fernandez-Vizarra and Eleonora Lamantea and Silvia Marchet and Lucia Morandi and Maurizio Moggio and Rosalba Carrozzo and Alessandra Torraco and Daria Diodato and Strom, {Tim M.} and Thomas Meitinger and Pinar Tekturk and Zuhal Yapici and Fathiya Al-Murshedi and Rene Stevens and Rodenburg, {Richard J.} and Costanza Lamperti and Anna Ardissone and Isabella Moroni and Graziella Uziel and Holger Prokisch and Taylor, {Robert W.} and Enrico Bertini and {Van Der Knaap}, {Marjo S.} and Daniele Ghezzi and Massimo Zeviani",
year = "2014",
doi = "10.1016/j.ajhg.2014.08.003",
language = "English",
volume = "95",
pages = "315--325",
journal = "American Journal of Human Genetics",
issn = "0002-9297",
publisher = "Cell Press",
number = "3",

}

TY - JOUR

T1 - Mutations in APOPT1, encoding a mitochondrial protein, cause cavitating leukoencephalopathy with cytochrome c oxidase deficiency

AU - Melchionda, Laura

AU - Haack, Tobias B.

AU - Hardy, Steven

AU - Abbink, Truus E M

AU - Fernandez-Vizarra, Erika

AU - Lamantea, Eleonora

AU - Marchet, Silvia

AU - Morandi, Lucia

AU - Moggio, Maurizio

AU - Carrozzo, Rosalba

AU - Torraco, Alessandra

AU - Diodato, Daria

AU - Strom, Tim M.

AU - Meitinger, Thomas

AU - Tekturk, Pinar

AU - Yapici, Zuhal

AU - Al-Murshedi, Fathiya

AU - Stevens, Rene

AU - Rodenburg, Richard J.

AU - Lamperti, Costanza

AU - Ardissone, Anna

AU - Moroni, Isabella

AU - Uziel, Graziella

AU - Prokisch, Holger

AU - Taylor, Robert W.

AU - Bertini, Enrico

AU - Van Der Knaap, Marjo S.

AU - Ghezzi, Daniele

AU - Zeviani, Massimo

PY - 2014

Y1 - 2014

N2 - Cytochrome c oxidase (COX) deficiency is a frequent biochemical abnormality in mitochondrial disorders, but a large fraction of cases remains genetically undetermined.Whole-exome sequencing led to the identification of APOPT1 mutations in two Italian sisters and in a third Turkish individual presenting severe COX deficiency. All three subjects presented a distinctive brain MRI pattern characterized by cavitating leukodystrophy, predominantly in the posterior region of the cerebral hemispheres. We then found APOPT1 mutations in three additional unrelated children, selected on the basis of these particular MRI features. All identified mutations predicted the synthesis of severely damaged protein variants. The clinical features of the six subjects varied widely from acute neurometabolic decompensation in late infancy to subtle neurological signs, which appeared in adolescence; all presented a chronic, long-surviving clinical course. We showed that APOPT1 is targeted to and localized within mitochondria by an N-terminal mitochondrial targeting sequence that is eventually cleaved off from the mature protein.We then showed that APOPT1 is virtually absent in fibroblasts cultured in standard conditions, but its levels increase by inhibiting the proteasome or after oxidative challenge. Mutant fibroblasts showed reduced amount of COX holocomplex and higher levels of reactive oxygen species, which both shifted toward control values by expressing a recombinant, wild-type APOPT1 cDNA. The shRNA-mediated knockdown of APOPT1 in myoblasts and fibroblasts caused dramatic decrease in cell viability. APOPT1 mutations are responsible for infantile or childhood-onset mitochondrial disease, hallmarked by the combination of profound COX deficiency with a distinctive neuroimaging presentation..

AB - Cytochrome c oxidase (COX) deficiency is a frequent biochemical abnormality in mitochondrial disorders, but a large fraction of cases remains genetically undetermined.Whole-exome sequencing led to the identification of APOPT1 mutations in two Italian sisters and in a third Turkish individual presenting severe COX deficiency. All three subjects presented a distinctive brain MRI pattern characterized by cavitating leukodystrophy, predominantly in the posterior region of the cerebral hemispheres. We then found APOPT1 mutations in three additional unrelated children, selected on the basis of these particular MRI features. All identified mutations predicted the synthesis of severely damaged protein variants. The clinical features of the six subjects varied widely from acute neurometabolic decompensation in late infancy to subtle neurological signs, which appeared in adolescence; all presented a chronic, long-surviving clinical course. We showed that APOPT1 is targeted to and localized within mitochondria by an N-terminal mitochondrial targeting sequence that is eventually cleaved off from the mature protein.We then showed that APOPT1 is virtually absent in fibroblasts cultured in standard conditions, but its levels increase by inhibiting the proteasome or after oxidative challenge. Mutant fibroblasts showed reduced amount of COX holocomplex and higher levels of reactive oxygen species, which both shifted toward control values by expressing a recombinant, wild-type APOPT1 cDNA. The shRNA-mediated knockdown of APOPT1 in myoblasts and fibroblasts caused dramatic decrease in cell viability. APOPT1 mutations are responsible for infantile or childhood-onset mitochondrial disease, hallmarked by the combination of profound COX deficiency with a distinctive neuroimaging presentation..

UR - http://www.scopus.com/inward/record.url?scp=84908254396&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84908254396&partnerID=8YFLogxK

U2 - 10.1016/j.ajhg.2014.08.003

DO - 10.1016/j.ajhg.2014.08.003

M3 - Article

VL - 95

SP - 315

EP - 325

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

SN - 0002-9297

IS - 3

ER -