Nature Genetics
35, 90 - 96 (2003)
Published online: 3 August 2003; | doi:10.1038/ng1224
Mutations associated with neutropenia in dogs and humans disrupt intracellular transport of neutrophil elastaseKathleen F Benson1, Feng-Qian Li1, Richard E Person2, Dalila Albani1, 5, Zhijun Duan1, Jeremy Wechsler1, 5, Kimberly Meade-White1, 5, Kayleen Williams1, Gregory M Acland3, Glenn Niemeyer4, Clinton D Lothrop4
& Marshall Horwitz11
Division of Medical Genetics / Department of Medicine, University of Washington School of Medicine, Box 357720, 1705 NE Pacific Street, HSB-K236B, Seattle, Washington 98195, USA. 2
Department of Pathology, University of Washington School of Medicine, Box 357720, 1705 NE Pacific Street, HSB-K236B, Seattle, Washington 98195, USA. 3
College of Veterinary Medicine, Cornell University, Ithaca, New York 14853, USA. 4
College of Veterinary Medicine, Auburn University, Auburn, Alabama 36849, USA. 5
Present addresses: Cabinet Beau de Loménie, 59800 Lille, France (D.A.); Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, Hamilton, Montana 59840, USA (K.M.-W.); University of Miami School of Medicine, Miami, Florida 33101, USA (J.W.).
Correspondence should be addressed to Marshall Horwitz horwitz@u.washington.eduCyclic hematopoiesis is a stem cell disease in which the number of neutrophils and other blood cells oscillates in weekly phases. Autosomal dominant mutations of ELA2, encoding the protease neutrophil elastase1, found in lysosome-like granules, cause cyclic hematopoiesis2 and most cases of the pre-leukemic disorder severe congenital neutropenia (SCN; ref. 3) in humans. Over 20 different mutations of neutrophil elastase have been identified, but their consequences are elusive, because they confer no consistent effects on enzymatic activity4. The similar autosomal recessive disease of dogs, canine cyclic hematopoiesis5, is not caused by mutations in ELA2 (data not shown). Here we show that homozygous mutation of the gene encoding the dog adaptor protein complex 3 (AP3)  -subunit, directing trans-Golgi export of transmembrane cargo proteins to lysosomes, causes canine cyclic hematopoiesis. C-terminal processing of neutrophil elastase exposes an AP3 interaction signal responsible for redirecting neutrophil elastase trafficking from membranes to granules. Disruption of either neutrophil elastase or AP3 perturbs the intracellular trafficking of neutrophil elastase. Most mutations in ELA2 that cause human cyclic hematopoiesis prevent membrane localization of neutrophil elastase, whereas most mutations in ELA2 that cause SCN lead to exclusive membrane localization.
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1A-adaptin-deficient mice: lethality, loss of AP-1 binding and rerouting of mannose 6-phosphate receptors
