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Blood, 1 October 2000, Vol. 96, No. 7, pp. 2317-2322
PLENARY PAPER
Mutations in the gene encoding neutrophil elastase in
congenital and cyclic neutropenia
David C. Dale,
Richard E. Person,
Audrey Anna Bolyard,
Andrew G. Aprikyan,
Cindy Bos,
Mary Ann Bonilla,
Laurence A. Boxer,
George Kannourakis,
Cornelia Zeidler,
Karl Welte,
Kathleen F. Benson, and
Marshall Horwitz
From the Divisions of Hematology and Medical Genetics,
Department of Medicine and the Markey Molecular Medicine Center,
University of Washington School of Medicine, Seattle, WA; St Barnabas
Medical Center, West Orange, NJ; University of Michigan, Ann Arbor, MI;
University of Ballarat, Ballarat, Australia; and Medizinische
Hochschule, Hannover, Germany.
Congenital neutropenia and cyclic neutropenia are disorders
of neutrophil production predisposing patients to recurrent bacterial infections. Recently the locus for autosomal dominant cyclic
neutropenia was mapped to chromosome 19p13.3, and this disease is
now attributable to mutations of the gene encoding neutrophil elastase
(the ELA2 gene). The authors hypothesized that congenital
neutropenia is also due to mutations of neutrophil elastase.
Patients with congenital neutropenia, cyclic neutropenia, or
Shwachman-Diamond syndrome were referred to the Severe Chronic
Neutropenia International Registry. Referring physicians provided
hematologic and clinical data. Mutational analysis was performed by
sequencing polymerase chain reaction (PCR)-amplified genomic DNA for
each of the 5 exons of the neutrophil ELA2 gene and 20 bases of the flanking regions. RNA from bone marrow mononuclear cells
was used to determine if the affected patients expressed both the
normal and the abnormal transcript. Twenty-two of 25 patients with
congenital neutropenia had 18 different heterozygous mutations. Four of
4 patients with cyclic neutropenia and 0 of 3 patients with
Shwachman-Diamond syndrome had mutations. For 5 patients with
congenital neutropenia having mutations predicted to alter RNA splicing
or transcript structure, reverse transcriptase-PCR showed
expression of both normal and abnormal transcripts. In cyclic
neutropenia, the mutations appeared to cluster near the active site of
the molecule, whereas the opposite face was predominantly affected by
the mutations found in congenital neutropenia. This study indicates
that mutations of the gene encoding neutrophil elastase are probably
the most common cause for severe congenital neutropenia as well as the cause for sporadic and autosomal dominant cyclic neutropenia.
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Related Letter in Blood Online:
-
Significance of neutrophil elastase mutations versus G-CSF receptor mutations for leukemic progression of congenital neutropenia
- Mirjam H. A. Hermans, Ivo P. Touw, David C. Dale, and Andrew Aprikyan
Blood 2001 97: 2185-2186.
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