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Mol Cell Biol, July 1998, p. 4324-4336, Vol. 18, No. 7
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

PEX12, the Pathogenic Gene of Group III Zellweger Syndrome: cDNA Cloning by Functional Complementation on a CHO Cell Mutant, Patient Analysis, and Characterization of Pex12p

Kanji Okumoto,1 Nobuyuki Shimozawa,2 Atsusi Kawai,1 Shigehiko Tamura,1 Toshiro Tsukamoto,3 Takashi Osumi,3 Hugo Moser,4 Ronald J. A. Wanders,5 Yasuyuki Suzuki,2 Naomi Kondo,2 and Yukio Fujiki1 6 *

Department of Biology, Faculty of Science, Kyushu University, Fukuoka 812-8581,1 Department of Pediatrics, Gifu University School of Medicine, Gifu 500-8076,2 Department of Life Science, Himeji Institute of Technology, Kamigori, Hyogo 678-1297,3 and CREST, Japan Science and Technology Corporation, Tokyo 170-0013,6 Japan; Kennedy-Krieger Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland 212054; and Department of Pediatrics, Academic Medical Centre, University of Amsterdam, 1100DE Amsterdam, The Netherlands5

Received 24 October 1997/Returned for modification 16 December 1997/Accepted 26 March 1998

Rat PEX12 cDNA was isolated by functional complementation of peroxisome deficiency of a mutant CHO cell line, ZP109 (K. Okumoto, A. Bogaki, K. Tateishi, T. Tsukamoto, T. Osumi, N. Shimozawa, Y. Suzuki, T. Orii, and Y. Fujiki, Exp. Cell Res. 233:11-20, 1997), using a transient transfection assay and an ectopic, readily visible marker, green fluorescent protein. This cDNA encodes a 359-amino-acid membrane protein of peroxisomes with two transmembrane segments and a cysteine-rich zinc finger, the RING motif. A stable transformant of ZP109 with the PEX12 was morphologically and biochemically restored for peroxisome biogenesis. Pex12p was shown by expression of bona fide as well as epitope-tagged Pex12p to expose both N- and C-terminal regions to the cytosol. Fibroblasts derived from patients with the peroxisome deficiency Zellweger syndrome of complementation group III (CG-III) were also complemented for peroxisome biogenesis with PEX12. Two unrelated patients of this group manifesting peroxisome deficiency disorders possessed homozygous, inactivating PEX12 mutations: in one, Arg180Thr by one point mutation, and in the other, deletion of two nucleotides in codons for 291Asn and 292Ser, creating an apparently unchanged codon for Asn and a codon 292 for termination. These results indicate that the gene encoding peroxisome assembly factor Pex12p is a pathogenic gene of CG-III peroxisome deficiency. Moreover, truncation and site mutation studies, including patient PEX12 analysis, demonstrated that the cytoplasmically oriented N- and C-terminal parts of Pex12p are essential for biological function.

* Corresponding author. Mailing address: Department of Biology, Kyushu University Faculty of Science, 6-10-1 Hakozaki, Higashi-ku, Fukuoka 812-8581, Japan. Phone: 81-92-642-2635. Fax: 81-92-642-4214 or -2645. E-mail: yfujiscb{at}mbox.nc.kyushu-u.ac.jp.

Mol Cell Biol, July 1998, p. 4324-4336, Vol. 18, No. 7
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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