title: 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 periodicity. Circulating neutrophils vary between almost normal numbers and zero. During intervals of neutropenia, affected individuals are at risk for opportunistic infection. 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 granules) is the target for protease inhibition by alpha1-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.
authors.affiliation: Division of Medical Genetics, University of Washington School of Medicine, Seattle, Washington, USA. horwitz@u.washington.edu
authors.forename: M
authors.initials: M
authors.lastname: Horwitz
authors.forename: K F
authors.initials: KF
authors.lastname: Benson
authors.forename: R E
authors.initials: RE
authors.lastname: Person
authors.forename: A G
authors.initials: AG
authors.lastname: Aprikyan
authors.forename: D C
authors.initials: DC
authors.lastname: Dale
mesh_terms: D001483:Base Sequence; D001683:Biological Clocks / Q000235:genetics*; D002874:Chromosome Mapping; D002888:Chromosomes, Human, Pair 19 / Q000235:genetics; D004252:DNA Mutational Analysis; D017931:DNA Primers / Q000235:genetics; D018076:DNA, Complementary / Q000235:genetics; D005260:Female; D005799:Genes, Dominant; D006410:Hematopoiesis / Q000235:genetics*; D006801:Humans; D019272:Leukocyte Elastase / Q000737:chemistry / Q000235:genetics*; D008297:Male; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D009503:Neutropenia / Q000097:blood / Q000201:enzymology* / Q000235:genetics*; D010375:Pedigree; D010507:Periodicity; D017434:Protein Structure, Tertiary
chemical_list: D017931:DNA Primers; D018076:DNA, Complementary; D019272:Leukocyte Elastase