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J. Biol. Chem., Vol. 281, Issue 17, 11894-11900, April 28, 2006

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A Mutation in Aminopeptidase N (CD13) Isolated from a Patient Suffering from Leukemia Leads to an Arrest in the Endoplasmic Reticulum^*

Marwan Alfalah¹, Michael P. Krahn, Gabi Wetzel, Stephan von Hörsten, Carmen Wolke^¶, Nigel Hooper^||, Thomas Kalinski^**, Sabine Krueger^**, Hassan Y. Naim, and Uwe Lendeckel^¶

From the Department of Physiological Chemistry, School of Veterinary Medicine, D-30559 Hannover, Germany, Department of Functional and Applied Anatomy, Hannover Medical School, D-30625 Hannover, Germany, ^¶Institute of Experimental Internal Medicine, Otto-von-Guericke University, D-39120 Magdeburg, Germany, ^||School of Biochemistry and Microbiology, University of Leeds, Leeds LS29 JT, United Kingdom, and ^**Institute of Pathology, Otto-von-Guericke University, D-39120 Magdeburg, Germany

Human aminopeptidase N (APN) is used as a routine marker for myelomonocytic cells in hematopoietic malignant disorders. Its gene and surface expressions are increased in cases of malignant transformation, inflammation, or T cell activation, whereas normal B and resting T cells lack detectable APN protein expression. In this study we elucidated the intracellular distribution, expression pattern, and enzymatic activity of a naturally occurring mutation in the coding region of the APN gene. At physiological temperatures the mutant protein is enzymatically inactive, persists as a mannose-rich polypeptide in the endoplasmic reticulum, and is ultimately degraded by an endoplasmic reticulum-associated degradation pathway. It shows in part the distinct behavior of a temperature-sensitive mutant with a permissive temperature of 32 °C, leading to correct sorting of the Golgi compartment accompanied by the acquisition of proper glycosylation but without reaching the cell-surface membrane and without regaining its enzymatic activity. Because the patient bearing this mutation suffered from leukemia, possible links to the pathogenesis of leukemia are discussed.

Received for publication, October 19, 2005 , and in revised form, January 18, 2006.

^* This work was supported by Grant Na 331/1-4 from the Deutsche Forschungsgemeinschaft, Bonn, Germany, and by Sonderforschungsbereich 621, Bonn, Germany (to H. Y. N.). 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: Dept. of Physiological Chemistry, School of Veterinary Medicine Hannover, Bünteweg 17, D-30559 Hannover, Germany. Tel.: 49-511-953-8786; Fax: 49-511-953-8585; E-mail: Marwan.Alfalah{at}tiho-hannover.de.

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