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Temperature sensitive acyl-CoA oxidase import in group A peroxisome biogenesis disorders
  1. Atsushi Imamuraa,b,
  2. Nobuyuki Shimozawaa,
  3. Yasuyuki Suzukia,
  4. Zhongyi Zhanga,
  5. Toshiro Tsukamotoc,
  6. Tadao Oriid,
  7. Takashi Osumic,
  8. Naomi Kondoa
  1. aDepartment of Paediatrics, Gifu University School of Medicine, 40 Tsukasa-machi, Gifu 500-8705, Japan, bDepartment of Paediatrics, Ogaki Municipal Hospital, Ogaki, Gifu 503-8502, Japan, cDepartment of Life Science, Himeji Institute of Technology, Kamigori, Hyogo 678-1297, Japan, dFaculty of Human Welfare, Chubu Gakuin University, Seki, Gifu 501-3936, Japan
  1. Dr Imamura,aimamura{at}cc.gifu-u.ac.jp

https://doi.org/10.1136/jmg.38.12.871

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    Editor—Peroxisome biogenesis disorders (PBDs) are lethal genetic diseases characterised by a number of peroxisomal metabolic abnormalities, including the oxidation of very long chain fatty acids (VLCFAs), biosynthesis of bile acids and plasmalogen, and detoxification of H2O2. Peroxisomal matrix proteins are synthesised on free polyribosomes and directed to the organelle by cis acting peroxisome targeting signals (PTSs). PTS1 is a C-terminal tripeptide Ser-Lys-Leu (SKL) sequence and later the consensus sequence was broadened to (S/A/C/K/N)-(K/R/H/Q/N/S)-L, based on subsequent studies. Acyl-CoA oxidase (AOX) has SKL and D bifunctional protein has AKL.1-4 PTS2 is an N-terminal cleavable peptide (-R/KLX5Q/HL) that resides in peroxisomal 3-ketoacyl CoA thiolase (PT), alkyl-dihydroxyacetonephosphate synthase, and phytanoyl-CoA hydroxylase.5-9 PBDs are genetically classified into at least 12 complementation groups (CGs) and each CG contains various clinical phenotypes, for example, Zellweger syndrome (ZS), neonatal adrenoleucodystrophy (NALD), and infantile Refsum disease (IRD).10 11 ZS patients have severe neurological defects, liver dysfunction, and renal cysts and die before 1 year of age. NALD patients have symptoms similar to ZS patients, but they survive a little longer, and IRD patients show milder abnormalities in the central nervous system and survive even longer. We identified the restoration of peroxisome biogenesis in a temperature sensitive (TS) manner in fibroblasts from milder forms of PBDs, that is, all IRD patients and some NALD patients belonging to groups CG-A (CG8), CG-C (CG4), CG-E (CG1), CG-F (CG10), CG-H, and CG6.12-15 In these cells, peroxisomes were formed at 30°C and biochemical activities of peroxisomes, including the oxidation of VLCFAs and dihydroxyacetonephosphate acyltransferase (DHAP-AT), and the import of peroxisomal enzymes, were also restored.16 However, virtually no peroxisomes were formed in ZS cells at 30°C and import of peroxisomal enzymes did not improve.16 Here, we elucidate temperature dependent import and processing …

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