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J. Biol. Chem., Vol. 282, Issue 42, 30373-30380, October 19, 2007

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PGAP1 Knock-out Mice Show Otocephaly and Male Infertility^*

Yasutaka Ueda, Ryo Yamaguchi, Masahito Ikawa, Masaru Okabe, Eiichi Morii^¶, Yusuke Maeda, and Taroh Kinoshita¹

From the Department of Immunoregulation and the Genome Information Research Center, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871 and the ^¶Department of Pathology, Osaka University Medical School, Yamada-oka 2-2, Suita, Osaka 565-0871, Japan

A palmitate linked to the inositol in glycosylphosphatidylinositol (GPI) is removed in the endoplasmic reticulum immediately after the conjugation of GPI with proteins in most cells. Previously, we identified PGAP1 (post GPI attachment to proteins 1) as a GPI inositoldeacylase that removes the palmitate from inositol. A defect in PGAP1 caused a delay in the transport of GPI-anchored proteins (GPI-APs) from the endoplasmic reticulum to the cell surface in Chinese hamster ovary cells, although the cell-surface expression of GPI-APs in the steady state was normal. Nevertheless, in most cells, GPI-APs undergo deacylation. To elucidate the biological significance of PGAP1 in vivo, we established PGAP1 knock-out mice. Most PGAP1 knock-out mice showed otocephaly, a developmental defect, and died right after birth. However, some survived with growth retardation. Male knock-out mice showed severely reduced fertility despite the capability of ejaculation. Their spermatozoa were normal in number, motility, and ability to ascend the uterus, but were unable to go into the oviduct. In vitro, PGAP1-deficient spermatozoa showed weak attachment to the zona pellucida and a severely diminished rate of fertilization. Therefore, an extra acyl chain in GPI anchors caused severe deleterious effects to development and sperm function.

Received for publication, July 9, 2007 , and in revised form, August 15, 2007.

^* This work was supported by grants from the Ministry of Education, Culture, Sports, Science, and Technology of Japan and the Core Research for Evolutional Science and Technology, Japan Science and Technology Agency. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed. Tel.: 81-6-6879-8328; Fax: 81-6-6875-5233; E-mail: tkinoshi{at}biken.osaka-u.ac.jp.

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				T. Kinoshita, M. Fujita, and Y. Maeda Biosynthesis, Remodelling and Functions of Mammalian GPI-anchored Proteins: Recent Progress J. Biochem., September 1, 2008; 144(3): 287 - 294. [Abstract] [Full Text] [PDF]