PMID- 10581030
OWN - NLM
STAT- MEDLINE
DCOM- 19991220
LR  - 20071114
IS  - 1061-4036 (Print)
IS  - 1061-4036 (Linking)
VI  - 23
IP  - 4
DP  - 1999 Dec
TI  - Mutations in ELA2, encoding neutrophil elastase, define a 21-day biological clock
      in cyclic haematopoiesis.
PG  - 433-6
AB  - 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.
FAU - Horwitz, M
AU  - Horwitz M
AD  - Division of Medical Genetics, University of Washington School of Medicine,
      Seattle, Washington, USA. horwitz@u.washington.edu
FAU - Benson, K F
AU  - Benson KF
FAU - Person, R E
AU  - Person RE
FAU - Aprikyan, A G
AU  - Aprikyan AG
FAU - Dale, D C
AU  - Dale DC
LA  - eng
GR  - DK18951/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - Nat Genet
JT  - Nature genetics
JID - 9216904
RN  - 0 (DNA Primers)
RN  - 0 (DNA, Complementary)
RN  - EC 3.4.21.37 (Leukocyte Elastase)
SB  - IM
MH  - Base Sequence
MH  - Biological Clocks/*genetics
MH  - Chromosome Mapping
MH  - Chromosomes, Human, Pair 19/genetics
MH  - DNA Mutational Analysis
MH  - DNA Primers/genetics
MH  - DNA, Complementary/genetics
MH  - Female
MH  - Genes, Dominant
MH  - Hematopoiesis/*genetics
MH  - Humans
MH  - Leukocyte Elastase/chemistry/*genetics
MH  - Male
MH  - Models, Molecular
MH  - Molecular Sequence Data
MH  - *Mutation
MH  - Neutropenia/blood/*enzymology/*genetics
MH  - Pedigree
MH  - Periodicity
MH  - Protein Structure, Tertiary
EDAT- 1999/12/02 09:00
MHDA- 2001/03/23 10:01
CRDT- 1999/12/02 09:00
PHST- 1999/12/02 09:00 [pubmed]
PHST- 2001/03/23 10:01 [medline]
PHST- 1999/12/02 09:00 [entrez]
AID - 10.1038/70544 [doi]
PST - ppublish
SO  - Nat Genet. 1999 Dec;23(4):433-6. doi: 10.1038/70544.