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Research article

Phenotype–genotype relationships in peroxisome biogenesis disorders of PEX1-defective complementation group 1 are defined by Pex1p–Pex6p interaction

Shigehiko TAMURA, Naomi MATSUMOTO, Atsushi IMAMURA, Nobuyuki SHIMOZAWA, Yasuyuki SUZUKI, Naomi KONDO, Yukio FUJIKI
Biochemical Journal Jul 15, 2001, 357 (2) 417-426; DOI: 10.1042/bj3570417
Shigehiko TAMURA
Department of Biology, Faculty of Sciences, Kyushu University Graduate School, 6-10-1 Hakozaki, Higashi-ku, Fukuoka 812-8581, Japan
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Naomi MATSUMOTO
Department of Biology, Faculty of Sciences, Kyushu University Graduate School, 6-10-1 Hakozaki, Higashi-ku, Fukuoka 812-8581, JapanCREST, Japan Science and Technology Corporation, 1-17-8 Higashi Ikebukuro, Toshima-ku, Tokyo 170-0013, Japan
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Atsushi IMAMURA
Department of Pediatrics, Gifu University Faculty of Medicine, 40 Tsukasa-cho, Gifu 500-8076, Japan
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Nobuyuki SHIMOZAWA
Department of Pediatrics, Gifu University Faculty of Medicine, 40 Tsukasa-cho, Gifu 500-8076, Japan
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Yasuyuki SUZUKI
Department of Pediatrics, Gifu University Faculty of Medicine, 40 Tsukasa-cho, Gifu 500-8076, Japan
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Naomi KONDO
Department of Pediatrics, Gifu University Faculty of Medicine, 40 Tsukasa-cho, Gifu 500-8076, Japan
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Yukio FUJIKI
Department of Biology, Faculty of Sciences, Kyushu University Graduate School, 6-10-1 Hakozaki, Higashi-ku, Fukuoka 812-8581, JapanCREST, Japan Science and Technology Corporation, 1-17-8 Higashi Ikebukuro, Toshima-ku, Tokyo 170-0013, Japan
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Abstract

The peroxisome biogenesis disorders (PBDs), including Zellweger syndrome (ZS), neonatal adrenoleucodystrophy (NALD) and infantile Refsum disease (IRD), are fatal autosomal recessive diseases caused by impaired peroxisome biogenesis, of which 12 genotypes have been reported. ZS patients manifest the severest clinical and biochemical abnormalities, whereas those with NALD and IRD show less severity and the mildest features respectively. We have reported previously that temperature-sensitive peroxisome assembly is responsible for the mildness of the clinical features of IRD. PEX1 is the causative gene for PBDs of complementation group E (CG-E, CG1 in the U.S.A. and Europe), the PBDs of highest incidence, encoding the peroxin Pex1p of the AAA ATPase family. It has been also reported that Pex1p and Pex6p interact with each other. In the present study we investigated phenotype–genotype relationships of CG1 PBDs. Pex1p from IRD such as Pex1p with the most frequently identified mutation at G843D was largely degraded in vivo at 37°C, whereas a normal level of Pex1p was detectable at the permissive temperature. In contrast, PEX1 proteins derived from ZS patients, including proteins with a mutation at L664P or the deletion of residues 634–690, were stably present at both temperatures. Pex1p-G843D interacted with Pex6p at approx. 50% of the level of normal Pex1p, whereas Pex1p from ZS patients mostly showing non-temperature-sensitive peroxisome biogenesis hardly bound to Pex6p. Taking these results together, we consider it most likely that the stability of Pex1p reflects temperature-sensitive peroxisome assembly in IRD fibroblasts. Failure in Pex1p–Pex6p interaction gives rise to more severe abnormalities, such as those manifested by patients with ZS.

  • AAA ATPase
  • infantile Refsum disease
  • temperature sensitivity
  • Zellweger syndrome

Footnotes

  • Abbreviations used: AOx, acyl-CoA oxidase; CG, complementation group; CHO, Chinese hamster ovary; IRD, infantile Refsum disease; NALD, neonatal adrenoleucodystrophy; PBDs, peroxisome biogenesis disorders; PMP70, 70kDa peroxisomal membrane protein; PNS, post-nuclear supernatant; PTS, peroxisome targeting signal; RT–PCR, reverse-transcriptase-mediated PCR; thiolase, 3-ketoacyl-CoA thiolase; ts, temperature-sensitive; ZS, Zellweger syndrome.

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July 2001

Volume: 357 Issue: 2

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Phenotype–genotype relationships in peroxisome biogenesis disorders of PEX1-defective complementation group 1 are defined by Pex1p–Pex6p interaction
Shigehiko TAMURA, Naomi MATSUMOTO, Atsushi IMAMURA, Nobuyuki SHIMOZAWA, Yasuyuki SUZUKI, Naomi KONDO, Yukio FUJIKI
Biochemical Journal Jul 2001, 357 (2) 417-426; DOI: 10.1042/bj3570417
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Phenotype–genotype relationships in peroxisome biogenesis disorders of PEX1-defective complementation group 1 are defined by Pex1p–Pex6p interaction
Shigehiko TAMURA, Naomi MATSUMOTO, Atsushi IMAMURA, Nobuyuki SHIMOZAWA, Yasuyuki SUZUKI, Naomi KONDO, Yukio FUJIKI
Biochemical Journal Jul 2001, 357 (2) 417-426; DOI: 10.1042/bj3570417

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Keywords

AAA ATPase
infantile Refsum disease
temperature sensitivity
Zellweger syndrome

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