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

Human cyclic haematopoiesis (cyclic neutropenia, MIM 162800) is an autosoma l dominant disease in which blood-cell production from the bone marrow osci llates with 21-day periodicity(1,2). Circulating neutrophils vary between a lmost normal numbers and zero. During intervals of neutropenia, affected in dividuals are at risk for opportunistic infection(3). 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 chromos ome 19p13.3. We identified 7 different single-base substitutions in the gen e (ELA2) encoding neutrophil elastase (EC 3.4.21.37, also known as leukocyt e 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 prote in predominantly found in neutrophil granules(4)) is the target for proteas e inhibition by alpha(1)-antitrypsin, and its unopposed release destroys ti ssue at sites of inflammation. We hypothesize that a perturbed interaction between neutrophil elastase and serpins or other substrates may regulate me chanisms governing the clock-like timing of haematopoiesis.