A homozygous mutation of C12orf65 causes spastic paraplegia with optic atrophy and neuropathy (SPG55)

Haruo Shimazaki, Yoshihisa Takiyama, Hiroyuki Ishiura, Chika Sakai, Yuichi Matsushima, Hideyuki Hatakeyama, Junko Honda, Kumi Sakoe, Tametou Naoi, Michito Namekawa, Yoko Fukuda, Yuji Takahashi, Jun Goto, Shoji Tsuji, Yu Ichi Goto, Imaharu Nakano

Research output: Contribution to journalArticle

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Abstract

Background: Autosomal recessive hereditary spastic paraplegias (AR-HSP) constitute a heterogeneous group of neurodegenerative diseases involving pyramidal tracts dysfunction. The genes responsible for many types of AR-HSPs remain unknown. We attempted to identify the gene responsible for AR-HSP with optic atrophy and neuropathy. Methods: The present study involved two patients in a consanguineous Japanese family. Neurologic examination and DNA analysis were performed for both patients, and a skin biopsy for one. We performed genome-wide linkage analysis involving single nucleotide polymorphism arrays, copy-number variation analysis, and exome sequencing. To clarify the mitochondrial functional alteration resulting from the identified mutation, we performed immunoblot analysis, mitochondrial protein synthesis assaying, blue native polyacrylamide gel electrophoresis (BN-PAGE) analysis, and respiratory enzyme activity assaying of cultured fibroblasts of the patient and a control. Results: We identified a homozygous nonsense mutation (c.394C>T, p.R132X) in C12orf65 in the two patients in this family. This C12orf65 mutation was not found in 74 Japanese AR-HSP index patients without any mutations in previously known HSP genes. This mutation resulted in marked reduction of mitochondrial protein synthesis, followed by functional and structural defects in respiratory complexes I and IV. Conclusions: This novel nonsense mutation in C12orf65 could cause AR-HSP with optic atrophy and neuropathy, resulting in a premature stop codon. The truncated C12orf65 protein must lead to a defect in mitochondrial protein synthesis and a reduction in the respiratory complex enzyme activity. Thus, dysfunction of mitochondrial translation could be one of the pathogenic mechanisms underlying HSPs.

Original languageEnglish
Pages (from-to)777-784
Number of pages8
JournalJournal of Medical Genetics
Volume49
Issue number12
DOIs
Publication statusPublished - Dec 1 2012
Externally publishedYes

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Hereditary Spastic Paraplegia
Nonsense Codon
Mitochondrial Proteins
Mutation
Genes
Exome
Electron Transport Complex I
Native Polyacrylamide Gel Electrophoresis
Pyramidal Tracts
Neurologic Examination
Enzymes
Neurodegenerative Diseases
Single Nucleotide Polymorphism
Fibroblasts
Spastic Paraplegia, Optic Atrophy, and Neuropathy
Genome
Biopsy
Skin
DNA
Proteins

All Science Journal Classification (ASJC) codes

  • Genetics
  • Genetics(clinical)

Cite this

A homozygous mutation of C12orf65 causes spastic paraplegia with optic atrophy and neuropathy (SPG55). / Shimazaki, Haruo; Takiyama, Yoshihisa; Ishiura, Hiroyuki; Sakai, Chika; Matsushima, Yuichi; Hatakeyama, Hideyuki; Honda, Junko; Sakoe, Kumi; Naoi, Tametou; Namekawa, Michito; Fukuda, Yoko; Takahashi, Yuji; Goto, Jun; Tsuji, Shoji; Goto, Yu Ichi; Nakano, Imaharu.

In: Journal of Medical Genetics, Vol. 49, No. 12, 01.12.2012, p. 777-784.

Research output: Contribution to journalArticle

Shimazaki, H, Takiyama, Y, Ishiura, H, Sakai, C, Matsushima, Y, Hatakeyama, H, Honda, J, Sakoe, K, Naoi, T, Namekawa, M, Fukuda, Y, Takahashi, Y, Goto, J, Tsuji, S, Goto, YI & Nakano, I 2012, 'A homozygous mutation of C12orf65 causes spastic paraplegia with optic atrophy and neuropathy (SPG55)', Journal of Medical Genetics, vol. 49, no. 12, pp. 777-784. https://doi.org/10.1136/jmedgenet-2012-101212
Shimazaki, Haruo ; Takiyama, Yoshihisa ; Ishiura, Hiroyuki ; Sakai, Chika ; Matsushima, Yuichi ; Hatakeyama, Hideyuki ; Honda, Junko ; Sakoe, Kumi ; Naoi, Tametou ; Namekawa, Michito ; Fukuda, Yoko ; Takahashi, Yuji ; Goto, Jun ; Tsuji, Shoji ; Goto, Yu Ichi ; Nakano, Imaharu. / A homozygous mutation of C12orf65 causes spastic paraplegia with optic atrophy and neuropathy (SPG55). In: Journal of Medical Genetics. 2012 ; Vol. 49, No. 12. pp. 777-784.
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T1 - A homozygous mutation of C12orf65 causes spastic paraplegia with optic atrophy and neuropathy (SPG55)

AU - Shimazaki, Haruo

AU - Takiyama, Yoshihisa

AU - Ishiura, Hiroyuki

AU - Sakai, Chika

AU - Matsushima, Yuichi

AU - Hatakeyama, Hideyuki

AU - Honda, Junko

AU - Sakoe, Kumi

AU - Naoi, Tametou

AU - Namekawa, Michito

AU - Fukuda, Yoko

AU - Takahashi, Yuji

AU - Goto, Jun

AU - Tsuji, Shoji

AU - Goto, Yu Ichi

AU - Nakano, Imaharu

PY - 2012/12/1

Y1 - 2012/12/1

N2 - Background: Autosomal recessive hereditary spastic paraplegias (AR-HSP) constitute a heterogeneous group of neurodegenerative diseases involving pyramidal tracts dysfunction. The genes responsible for many types of AR-HSPs remain unknown. We attempted to identify the gene responsible for AR-HSP with optic atrophy and neuropathy. Methods: The present study involved two patients in a consanguineous Japanese family. Neurologic examination and DNA analysis were performed for both patients, and a skin biopsy for one. We performed genome-wide linkage analysis involving single nucleotide polymorphism arrays, copy-number variation analysis, and exome sequencing. To clarify the mitochondrial functional alteration resulting from the identified mutation, we performed immunoblot analysis, mitochondrial protein synthesis assaying, blue native polyacrylamide gel electrophoresis (BN-PAGE) analysis, and respiratory enzyme activity assaying of cultured fibroblasts of the patient and a control. Results: We identified a homozygous nonsense mutation (c.394C>T, p.R132X) in C12orf65 in the two patients in this family. This C12orf65 mutation was not found in 74 Japanese AR-HSP index patients without any mutations in previously known HSP genes. This mutation resulted in marked reduction of mitochondrial protein synthesis, followed by functional and structural defects in respiratory complexes I and IV. Conclusions: This novel nonsense mutation in C12orf65 could cause AR-HSP with optic atrophy and neuropathy, resulting in a premature stop codon. The truncated C12orf65 protein must lead to a defect in mitochondrial protein synthesis and a reduction in the respiratory complex enzyme activity. Thus, dysfunction of mitochondrial translation could be one of the pathogenic mechanisms underlying HSPs.

AB - Background: Autosomal recessive hereditary spastic paraplegias (AR-HSP) constitute a heterogeneous group of neurodegenerative diseases involving pyramidal tracts dysfunction. The genes responsible for many types of AR-HSPs remain unknown. We attempted to identify the gene responsible for AR-HSP with optic atrophy and neuropathy. Methods: The present study involved two patients in a consanguineous Japanese family. Neurologic examination and DNA analysis were performed for both patients, and a skin biopsy for one. We performed genome-wide linkage analysis involving single nucleotide polymorphism arrays, copy-number variation analysis, and exome sequencing. To clarify the mitochondrial functional alteration resulting from the identified mutation, we performed immunoblot analysis, mitochondrial protein synthesis assaying, blue native polyacrylamide gel electrophoresis (BN-PAGE) analysis, and respiratory enzyme activity assaying of cultured fibroblasts of the patient and a control. Results: We identified a homozygous nonsense mutation (c.394C>T, p.R132X) in C12orf65 in the two patients in this family. This C12orf65 mutation was not found in 74 Japanese AR-HSP index patients without any mutations in previously known HSP genes. This mutation resulted in marked reduction of mitochondrial protein synthesis, followed by functional and structural defects in respiratory complexes I and IV. Conclusions: This novel nonsense mutation in C12orf65 could cause AR-HSP with optic atrophy and neuropathy, resulting in a premature stop codon. The truncated C12orf65 protein must lead to a defect in mitochondrial protein synthesis and a reduction in the respiratory complex enzyme activity. Thus, dysfunction of mitochondrial translation could be one of the pathogenic mechanisms underlying HSPs.

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