A newly identified mutation in the PEX26 gene is associated with a milder form of Zellweger spectrum disorder

Akemi J. Tanaka, Kanji Okumoto, Shigehiko Tamura, Yuichi Abe, Yoel Hirsch, Liyong Deng, Joseph Ekstein, Wendy K. Chung, Yukio Fujiki

研究成果: ジャーナルへの寄稿記事

抄録

Using clinical exome sequencing (ES), we identified an autosomal recessive missense variant, c.153C>A (p.F51L), in the peroxisome biogenesis factor 26 gene (PEX26) in a 19-yr-old female of Ashkenazi Jewish descent who was referred for moderate to severe hearing loss. The proband and three affected siblings are all homozygous for the c.153C>A variant. Skin fibroblasts from this patient show normal morphology in immu-nostaining of matrix proteins, although the level of catalase was elevated. Import rate of matrix proteins was significantly decreased in the patient-derived fibroblasts. Binding of Pex26-F51L to the AAA ATPase peroxins, Pex1 and Pex6, is severely impaired and affects peroxisome assembly. Moreover, Pex26 in the patient’s fibroblasts is reduced to ∼30% of the control, suggesting that Pex26-F51L is unstable in cells. In the patient’s fibroblasts, peroxisome-targeting signal 1 (PTS1) proteins, PTS2 protein 3-ketoacyl-CoA thiolase, and catalase are present in a punctate staining pattern at 37°C and in a diffuse pattern at 42°C, suggesting that these matrix proteins are not imported to peroxisomes in a temperature-sensitive manner. Analysis of peroxisomal metabolism in the patient’s fibroblasts showed that the level of docosahexaenoic acid (DHA) (C22:6n-3) in ether phospholipids is decreased, whereas other lipid metabolism, including peroxisomal fatty acid β-oxidation, is normal. Collectively, the functional data support the mild phenotype of nonsyndromic hearing loss in patients harboring the F51L variant in PEX26.

元の言語英語
記事番号a003483
ジャーナルCold Spring Harbor Molecular Case Studies
5
発行部数1
DOI
出版物ステータス出版済み - 1 1 2019

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Zellweger Syndrome
Peroxisomes
Fibroblasts
Mutation
Genes
Catalase
Proteins
Phospholipid Ethers
Acetyl-CoA C-Acyltransferase
Exome
Docosahexaenoic Acids
Lipid Metabolism
Hearing Loss
Adenosine Triphosphatases
Siblings
Fatty Acids
Staining and Labeling
Phenotype
Skin
Temperature

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Medicine
  • Genetics
  • Genetics(clinical)

これを引用

A newly identified mutation in the PEX26 gene is associated with a milder form of Zellweger spectrum disorder. / Tanaka, Akemi J.; Okumoto, Kanji; Tamura, Shigehiko; Abe, Yuichi; Hirsch, Yoel; Deng, Liyong; Ekstein, Joseph; Chung, Wendy K.; Fujiki, Yukio.

:: Cold Spring Harbor Molecular Case Studies, 巻 5, 番号 1, a003483, 01.01.2019.

研究成果: ジャーナルへの寄稿記事

Tanaka, Akemi J. ; Okumoto, Kanji ; Tamura, Shigehiko ; Abe, Yuichi ; Hirsch, Yoel ; Deng, Liyong ; Ekstein, Joseph ; Chung, Wendy K. ; Fujiki, Yukio. / A newly identified mutation in the PEX26 gene is associated with a milder form of Zellweger spectrum disorder. :: Cold Spring Harbor Molecular Case Studies. 2019 ; 巻 5, 番号 1.
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title = "A newly identified mutation in the PEX26 gene is associated with a milder form of Zellweger spectrum disorder",
abstract = "Using clinical exome sequencing (ES), we identified an autosomal recessive missense variant, c.153C>A (p.F51L), in the peroxisome biogenesis factor 26 gene (PEX26) in a 19-yr-old female of Ashkenazi Jewish descent who was referred for moderate to severe hearing loss. The proband and three affected siblings are all homozygous for the c.153C>A variant. Skin fibroblasts from this patient show normal morphology in immu-nostaining of matrix proteins, although the level of catalase was elevated. Import rate of matrix proteins was significantly decreased in the patient-derived fibroblasts. Binding of Pex26-F51L to the AAA ATPase peroxins, Pex1 and Pex6, is severely impaired and affects peroxisome assembly. Moreover, Pex26 in the patient’s fibroblasts is reduced to ∼30{\%} of the control, suggesting that Pex26-F51L is unstable in cells. In the patient’s fibroblasts, peroxisome-targeting signal 1 (PTS1) proteins, PTS2 protein 3-ketoacyl-CoA thiolase, and catalase are present in a punctate staining pattern at 37°C and in a diffuse pattern at 42°C, suggesting that these matrix proteins are not imported to peroxisomes in a temperature-sensitive manner. Analysis of peroxisomal metabolism in the patient’s fibroblasts showed that the level of docosahexaenoic acid (DHA) (C22:6n-3) in ether phospholipids is decreased, whereas other lipid metabolism, including peroxisomal fatty acid β-oxidation, is normal. Collectively, the functional data support the mild phenotype of nonsyndromic hearing loss in patients harboring the F51L variant in PEX26.",
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T1 - A newly identified mutation in the PEX26 gene is associated with a milder form of Zellweger spectrum disorder

AU - Tanaka, Akemi J.

AU - Okumoto, Kanji

AU - Tamura, Shigehiko

AU - Abe, Yuichi

AU - Hirsch, Yoel

AU - Deng, Liyong

AU - Ekstein, Joseph

AU - Chung, Wendy K.

AU - Fujiki, Yukio

PY - 2019/1/1

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N2 - Using clinical exome sequencing (ES), we identified an autosomal recessive missense variant, c.153C>A (p.F51L), in the peroxisome biogenesis factor 26 gene (PEX26) in a 19-yr-old female of Ashkenazi Jewish descent who was referred for moderate to severe hearing loss. The proband and three affected siblings are all homozygous for the c.153C>A variant. Skin fibroblasts from this patient show normal morphology in immu-nostaining of matrix proteins, although the level of catalase was elevated. Import rate of matrix proteins was significantly decreased in the patient-derived fibroblasts. Binding of Pex26-F51L to the AAA ATPase peroxins, Pex1 and Pex6, is severely impaired and affects peroxisome assembly. Moreover, Pex26 in the patient’s fibroblasts is reduced to ∼30% of the control, suggesting that Pex26-F51L is unstable in cells. In the patient’s fibroblasts, peroxisome-targeting signal 1 (PTS1) proteins, PTS2 protein 3-ketoacyl-CoA thiolase, and catalase are present in a punctate staining pattern at 37°C and in a diffuse pattern at 42°C, suggesting that these matrix proteins are not imported to peroxisomes in a temperature-sensitive manner. Analysis of peroxisomal metabolism in the patient’s fibroblasts showed that the level of docosahexaenoic acid (DHA) (C22:6n-3) in ether phospholipids is decreased, whereas other lipid metabolism, including peroxisomal fatty acid β-oxidation, is normal. Collectively, the functional data support the mild phenotype of nonsyndromic hearing loss in patients harboring the F51L variant in PEX26.

AB - Using clinical exome sequencing (ES), we identified an autosomal recessive missense variant, c.153C>A (p.F51L), in the peroxisome biogenesis factor 26 gene (PEX26) in a 19-yr-old female of Ashkenazi Jewish descent who was referred for moderate to severe hearing loss. The proband and three affected siblings are all homozygous for the c.153C>A variant. Skin fibroblasts from this patient show normal morphology in immu-nostaining of matrix proteins, although the level of catalase was elevated. Import rate of matrix proteins was significantly decreased in the patient-derived fibroblasts. Binding of Pex26-F51L to the AAA ATPase peroxins, Pex1 and Pex6, is severely impaired and affects peroxisome assembly. Moreover, Pex26 in the patient’s fibroblasts is reduced to ∼30% of the control, suggesting that Pex26-F51L is unstable in cells. In the patient’s fibroblasts, peroxisome-targeting signal 1 (PTS1) proteins, PTS2 protein 3-ketoacyl-CoA thiolase, and catalase are present in a punctate staining pattern at 37°C and in a diffuse pattern at 42°C, suggesting that these matrix proteins are not imported to peroxisomes in a temperature-sensitive manner. Analysis of peroxisomal metabolism in the patient’s fibroblasts showed that the level of docosahexaenoic acid (DHA) (C22:6n-3) in ether phospholipids is decreased, whereas other lipid metabolism, including peroxisomal fatty acid β-oxidation, is normal. Collectively, the functional data support the mild phenotype of nonsyndromic hearing loss in patients harboring the F51L variant in PEX26.

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