ACO2 homozygous missense mutation associated with complicated hereditary spastic paraplegia

Christian G. Bouwkamp; Zaid Afawi; Aviva Fattal-Valevski; Inge E. Krabbendam; Stefano Rivetti; Rafik Masalha; Marialuisa Quadri; Guido J. Breedveld; Hanna Mandel; Muhammad Abu Tailakh; H. Berna Beverloo; Giovanni Stevanin; Alexis Brice; Wilfred F.J. Van IJcken; Meike W. Vernooij; Amalia M. Dolga; Femke M.S. De Vrij; Vincenzo Bonifati; Steven A. Kushner

doi:10.1212/NXG.0000000000000223

ACO2 homozygous missense mutation associated with complicated hereditary spastic paraplegia

Christian G. Bouwkamp, Zaid Afawi, Aviva Fattal-Valevski, Inge E. Krabbendam, Stefano Rivetti, Rafik Masalha, Marialuisa Quadri, Guido J. Breedveld, Hanna Mandel, Muhammad Abu Tailakh, H. Berna Beverloo, Giovanni Stevanin, Alexis Brice, Wilfred F.J. Van IJcken, Meike W. Vernooij, Amalia M. Dolga, Femke M.S. De Vrij, Vincenzo Bonifati, Steven A. Kushner

Medical School for International Health

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18 Scopus citations

Abstract

Objective: To identify the clinical characteristics and genetic etiology of a family affected with hereditary spastic paraplegia (HSP). Methods: Clinical, genetic, and functional analyses involving genome-wide linkage coupled to wholeexome sequencing in a consanguineous family with complicated HSP. Results: A homozygous missense mutation was identified in the ACO2 gene (c.1240T>G p.Phe414Val) that segregated with HSP complicated by intellectual disability and microcephaly. Lymphoblastoid cell lines of homozygous carrier patients revealed significantly decreased activity of the mitochondrial aconitase enzyme and defective mitochondrial respiration. ACO2 encodes mitochondrial aconitase, an essential enzyme in the Krebs cycle. Recessive mutations in this gene have been previously associated with cerebellar ataxia. Conclusions: Our findings nominate ACO2 as a disease-causing gene for autosomal recessive complicated HSP and provide further support for the central role of mitochondrial defects in the pathogenesis of HSP.

Original language	English
Article number	e223
Journal	Neurology: Genetics
Volume	4
Issue number	2
DOIs	https://doi.org/10.1212/NXG.0000000000000223
State	Published - 1 Apr 2018

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Bouwkamp, C. G., Afawi, Z., Fattal-Valevski, A., Krabbendam, I. E., Rivetti, S., Masalha, R., Quadri, M., Breedveld, G. J., Mandel, H., Tailakh, M. A., Beverloo, H. B., Stevanin, G., Brice, A., Van IJcken, W. F. J., Vernooij, M. W., Dolga, A. M., De Vrij, F. M. S., Bonifati, V., & Kushner, S. A. (2018). ACO2 homozygous missense mutation associated with complicated hereditary spastic paraplegia. Neurology: Genetics, 4(2), [e223]. https://doi.org/10.1212/NXG.0000000000000223

Bouwkamp, Christian G. ; Afawi, Zaid ; Fattal-Valevski, Aviva ; Krabbendam, Inge E. ; Rivetti, Stefano ; Masalha, Rafik ; Quadri, Marialuisa ; Breedveld, Guido J. ; Mandel, Hanna ; Tailakh, Muhammad Abu ; Beverloo, H. Berna ; Stevanin, Giovanni ; Brice, Alexis ; Van IJcken, Wilfred F.J. ; Vernooij, Meike W. ; Dolga, Amalia M. ; De Vrij, Femke M.S. ; Bonifati, Vincenzo ; Kushner, Steven A. / ACO2 homozygous missense mutation associated with complicated hereditary spastic paraplegia. In: Neurology: Genetics. 2018 ; Vol. 4, No. 2.

@article{1306956d0d6b4b1b8e15fa0d8dad02cb,

title = "ACO2 homozygous missense mutation associated with complicated hereditary spastic paraplegia",

abstract = "Objective: To identify the clinical characteristics and genetic etiology of a family affected with hereditary spastic paraplegia (HSP). Methods: Clinical, genetic, and functional analyses involving genome-wide linkage coupled to wholeexome sequencing in a consanguineous family with complicated HSP. Results: A homozygous missense mutation was identified in the ACO2 gene (c.1240T>G p.Phe414Val) that segregated with HSP complicated by intellectual disability and microcephaly. Lymphoblastoid cell lines of homozygous carrier patients revealed significantly decreased activity of the mitochondrial aconitase enzyme and defective mitochondrial respiration. ACO2 encodes mitochondrial aconitase, an essential enzyme in the Krebs cycle. Recessive mutations in this gene have been previously associated with cerebellar ataxia. Conclusions: Our findings nominate ACO2 as a disease-causing gene for autosomal recessive complicated HSP and provide further support for the central role of mitochondrial defects in the pathogenesis of HSP.",

author = "Bouwkamp, {Christian G.} and Zaid Afawi and Aviva Fattal-Valevski and Krabbendam, {Inge E.} and Stefano Rivetti and Rafik Masalha and Marialuisa Quadri and Breedveld, {Guido J.} and Hanna Mandel and Tailakh, {Muhammad Abu} and Beverloo, {H. Berna} and Giovanni Stevanin and Alexis Brice and {Van IJcken}, {Wilfred F.J.} and Vernooij, {Meike W.} and Dolga, {Amalia M.} and {De Vrij}, {Femke M.S.} and Vincenzo Bonifati and Kushner, {Steven A.}",

note = "Funding Information: The Article Processing Charge was funded by the authors. Funding Information: This study was funded in part by the Netherlands Organization for Scientific Research (NWO) and Netherlands Organisation for Health Research and Development (ZonMw) to S.A.K. and V.B., the Royal Netherlands Academy of Arts and Sciences (KNAW) Sara van Dam Foundation to C.G.B. and Z.A., the NeuroBasic-PharmaPhenomics consortium to S.A.K., and Stichting ParkinsonFonds (The Netherlands) to V.B. Publisher Copyright: {\textcopyright} 2018 The Author(s).",

year = "2018",

month = apr,

day = "1",

doi = "10.1212/NXG.0000000000000223",

language = "English",

volume = "4",

journal = "Neurology: Genetics",

issn = "2376-7839",

publisher = "Lippincott Williams and Wilkins",

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Bouwkamp, CG, Afawi, Z, Fattal-Valevski, A, Krabbendam, IE, Rivetti, S, Masalha, R, Quadri, M, Breedveld, GJ, Mandel, H, Tailakh, MA, Beverloo, HB, Stevanin, G, Brice, A, Van IJcken, WFJ, Vernooij, MW, Dolga, AM, De Vrij, FMS, Bonifati, V & Kushner, SA 2018, 'ACO2 homozygous missense mutation associated with complicated hereditary spastic paraplegia', Neurology: Genetics, vol. 4, no. 2, e223. https://doi.org/10.1212/NXG.0000000000000223

ACO2 homozygous missense mutation associated with complicated hereditary spastic paraplegia. / Bouwkamp, Christian G.; Afawi, Zaid; Fattal-Valevski, Aviva; Krabbendam, Inge E.; Rivetti, Stefano; Masalha, Rafik; Quadri, Marialuisa; Breedveld, Guido J.; Mandel, Hanna; Tailakh, Muhammad Abu; Beverloo, H. Berna; Stevanin, Giovanni; Brice, Alexis; Van IJcken, Wilfred F.J.; Vernooij, Meike W.; Dolga, Amalia M.; De Vrij, Femke M.S.; Bonifati, Vincenzo; Kushner, Steven A.

In: Neurology: Genetics, Vol. 4, No. 2, e223, 01.04.2018.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - ACO2 homozygous missense mutation associated with complicated hereditary spastic paraplegia

AU - Bouwkamp, Christian G.

AU - Afawi, Zaid

AU - Fattal-Valevski, Aviva

AU - Krabbendam, Inge E.

AU - Rivetti, Stefano

AU - Masalha, Rafik

AU - Quadri, Marialuisa

AU - Breedveld, Guido J.

AU - Mandel, Hanna

AU - Tailakh, Muhammad Abu

AU - Beverloo, H. Berna

AU - Stevanin, Giovanni

AU - Brice, Alexis

AU - Van IJcken, Wilfred F.J.

AU - Vernooij, Meike W.

AU - Dolga, Amalia M.

AU - De Vrij, Femke M.S.

AU - Bonifati, Vincenzo

AU - Kushner, Steven A.

N1 - Funding Information: The Article Processing Charge was funded by the authors. Funding Information: This study was funded in part by the Netherlands Organization for Scientific Research (NWO) and Netherlands Organisation for Health Research and Development (ZonMw) to S.A.K. and V.B., the Royal Netherlands Academy of Arts and Sciences (KNAW) Sara van Dam Foundation to C.G.B. and Z.A., the NeuroBasic-PharmaPhenomics consortium to S.A.K., and Stichting ParkinsonFonds (The Netherlands) to V.B. Publisher Copyright: © 2018 The Author(s).

PY - 2018/4/1

Y1 - 2018/4/1

N2 - Objective: To identify the clinical characteristics and genetic etiology of a family affected with hereditary spastic paraplegia (HSP). Methods: Clinical, genetic, and functional analyses involving genome-wide linkage coupled to wholeexome sequencing in a consanguineous family with complicated HSP. Results: A homozygous missense mutation was identified in the ACO2 gene (c.1240T>G p.Phe414Val) that segregated with HSP complicated by intellectual disability and microcephaly. Lymphoblastoid cell lines of homozygous carrier patients revealed significantly decreased activity of the mitochondrial aconitase enzyme and defective mitochondrial respiration. ACO2 encodes mitochondrial aconitase, an essential enzyme in the Krebs cycle. Recessive mutations in this gene have been previously associated with cerebellar ataxia. Conclusions: Our findings nominate ACO2 as a disease-causing gene for autosomal recessive complicated HSP and provide further support for the central role of mitochondrial defects in the pathogenesis of HSP.

AB - Objective: To identify the clinical characteristics and genetic etiology of a family affected with hereditary spastic paraplegia (HSP). Methods: Clinical, genetic, and functional analyses involving genome-wide linkage coupled to wholeexome sequencing in a consanguineous family with complicated HSP. Results: A homozygous missense mutation was identified in the ACO2 gene (c.1240T>G p.Phe414Val) that segregated with HSP complicated by intellectual disability and microcephaly. Lymphoblastoid cell lines of homozygous carrier patients revealed significantly decreased activity of the mitochondrial aconitase enzyme and defective mitochondrial respiration. ACO2 encodes mitochondrial aconitase, an essential enzyme in the Krebs cycle. Recessive mutations in this gene have been previously associated with cerebellar ataxia. Conclusions: Our findings nominate ACO2 as a disease-causing gene for autosomal recessive complicated HSP and provide further support for the central role of mitochondrial defects in the pathogenesis of HSP.

UR - http://www.scopus.com/inward/record.url?scp=85048717240&partnerID=8YFLogxK

U2 - 10.1212/NXG.0000000000000223

DO - 10.1212/NXG.0000000000000223

M3 - Article

C2 - 29577077

AN - SCOPUS:85048717240

VL - 4

JO - Neurology: Genetics

JF - Neurology: Genetics

SN - 2376-7839

IS - 2

M1 - e223

ER -

ACO2 homozygous missense mutation associated with complicated hereditary spastic paraplegia

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