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Mutations in ELA2, encoding neutrophil elastase, define a 21-day biological clock in cyclic haematopoiesis

Abstract

Human cyclic haematopoiesis (cyclic neutropenia, MIM 162800) is an autosomal dominant disease in which blood-cell production from the bone marrow oscillates with 21-day periodicity1,2. Circulating neutrophils vary between almost normal numbers and zero. During intervals of neutropenia, affected individuals are at risk for opportunistic infection3. Monocytes, platelets, lymphocytes and reticulocytes also cycle with the same frequency. Here we use a genome-wide screen and positional cloning to map the locus to chromosome 19p13.3. We identified 7 different single-base substitutions in the gene (ELA2) encoding neutrophil elastase (EC 3.4.21.37, also known as leukocyte elastase, elastase 2 and medullasin), a serine protease of neutrophil and monocyte granules, on unique haplotypes in 13 of 13 families as well as a new mutation in a sporadic case. Neutrophil elastase (a 240-aa mature protein predominantly found in neutrophil granules4) is the target for protease inhibition by α1-antitrypsin, and its unopposed release destroys tissue at sites of inflammation. We hypothesize that a perturbed interaction between neutrophil elastase and serpins or other substrates may regulate mechanisms governing the clock-like timing of haematopoiesis.

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Figure 1: Pedigrees and haplotype summary.
Figure 2: DNA sequence analysis of mutations.
Figure 3: RT–PCR analysis from sporadic patient X1 bone marrow.
Figure 4: Position of mutations in the tertiary structure of neutrophil elastase.

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Acknowledgements

We thank the families for their help; A.-A. Bolyard, R. Oosterwyk, M. Lieschke and participating physicians of the Severe Chronic Neutropenia Registry; E. Lynch, G. Stamatoyannopoulos and M.-C. King for advice; and R. Livingston, S. Palmer, C. Bos, L. Keith and K. Stephens for contributions to an earlier phase of this study. This work was supported by the Markey Molecular Medicine Center and the Doris Duke Charitable Foundation grant T98006 (M.H.) and funding of the Registry by Amgen and NIH grant DK18951 (D.C.D.).

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Correspondence to Marshall Horwitz.

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Horwitz, M., Benson, K., Person, R. et al. Mutations in ELA2, encoding neutrophil elastase, define a 21-day biological clock in cyclic haematopoiesis. Nat Genet 23, 433–436 (1999). https://doi.org/10.1038/70544

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