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Prepublished online as a Blood First Edition Paper on May 24, 2002; DOI 10.1182/blood-2002-01-0060.
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Blood, 15 July 2002, Vol. 100, No. 2, pp. 707-709
BRIEF REPORT
Paternal mosaicism proves the pathogenic nature of mutations in
neutrophil elastase in severe congenital neutropenia
Phil J. Ancliff,
Rosemary
E. Gale,
Michael J. Watts,
Ri Liesner,
Ian M. Hann,
Stephan Strobel, and
David C. Linch
From the Departments of Haematology and Immunology,
University College London and Great Ormond Street Children's Hospital,
London, United Kingdom.
Heterozygous mutations in neutrophil elastase have been
detected in many sporadic cases of congenital neutropenia. However, a
convincing pathogenetic mechanism has not been established, and it is
unclear whether the effects of the mutant enzyme occur within the cell
of production or are paracrine in nature. The healthy father of a
patient was demonstrated to be mosaic for his daughter's Cys42Arg
elastase mutation. Using semiquantitative polymerase chain reaction,
approximately half of his T cells were shown to carry the mutation in
contrast to less than 10% of neutrophils. Individual hematopoietic
colonies grown from peripheral blood were heterozygous for the mutation
or were homozygous wild type. These results demonstrate that precursors
containing the mutation are selectively lost during myelopoiesis or
fail to develop into neutrophils. This is the first in vivo
confirmation of the pathogenic nature of elastase mutations in humans.
The normal neutrophil count in the father suggests that the mutant
elastase does not have paracrine effects.
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