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Volume 272, Number 30, Issue of July 25, 1997 pp. 18628-18635
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.

Mice Deficient in Lysosomal Acid Phosphatase Develop Lysosomal Storage in the Kidney and Central Nervous System

(Received for publication, March 31, 1997, and in revised form, May 20, 1997)

Paul Saftig , Dieter Hartmann ^¶ , Renate Lüllmann-Rauch ^¶ , Joachim Wolff , Meike Evers , Anja Köster , Michal Hetman , Kurt von Figura and Christoph Peters

From the  Zentrum Biochemie und Molekulare Zellbiologie, Abteilung Biochemie II, Universität Göttingen, Gosslerstrasse 12D, 37073 Göttingen, the ^¶ Anatomisches Institut, Christian Albrechts Universität Kiel, 24118 Kiel, and the  Zentrum Anatomie, Universität Göttingen, 37075 Göttingen, Federal Republic of Germany

Lysosomal acid phosphatase (LAP) is a tartrate-sensitive enzyme with ubiquitous expression. Neither the physiological substrates nor the functional significance is known. Mice with a deficiency of LAP generated by targeted disruption of the LAP gene are fertile and develop normally. Microscopic examination of various peripheral organs revealed progredient lysosomal storage in podocytes and tubular epithelial cells of the kidney, with regionally different ultrastructural appearance of the stored material. Within the central nervous system, lysosomal storage was detected to a regionally different extent in microglia, ependymal cells, and astroglia concomitant with the development of a progressive astrogliosis and microglial activation. Whereas behavioral and neuromotor analyses were unable to distinguish between control and deficient mice, ~7% of the deficient animals developed generalized seizures. From the age of 6 months onward, conspicuous alterations of bone structure became apparent, resulting in a kyphoscoliotic malformation of the lower thoracic vertebral column. We conclude from these findings that LAP has a unique function in only a subset of cells, where its deficiency causes the storage of a heterogeneously appearing material in lysosomes. The causal relationship of the enzyme defect to the clinical manifestations remains to be determined.

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