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Blood, 1 November 2001, Vol. 98, No. 9, pp. 2645-2650
CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
Mutations in the ELA2 gene encoding neutrophil
elastase are present in most patients with sporadic severe congenital
neutropenia but only in some patients with the familial form of
the disease
Phil J. Ancliff,
Rosemary
E. Gale,
Ri Liesner,
Ian M. Hann, and
David C. Linch
From the Department of Haematology, University College
London, and the Department of Haematology, Great Ormond Street
Hospital, London, United Kingdom.
Severe congenital neutropenia (SCN) was originally described as an
autosomal recessive disorder. Subsequently, autosomal dominant and
sporadic forms of the disease have been recognized. All forms are
manifest by persistent severe neutropenia and recurrent bacterial infection. In contrast, cyclical hematopoiesis is characterized by
periodic neutropenia inter-spaced with (near) normal neutrophil counts.
Recently, linkage analysis on 13 affected pedigrees identified chromosome 19p13.3 as the likely position for mutations in cyclical hematopoiesis. Heterozygous mutations in the ELA2 gene
encoding neutrophil elastase were detected in all families studied.
Further work also demonstrated mutations in ELA2 in
sporadic and autosomal dominant SCN. However, all mutations described
to date are heterozygous and thus appear to act in a dominant fashion,
which is inconsistent with an autosomal recessive disease. Therefore,
the current study investigated whether mutations in ELA2
could account for the disease phenotype in classical autosomal
recessive SCN and in the sporadic and autosomal dominant types. All 5 exons of ELA2 and their flanking introns were studied in 18 patients (3 autosomal recessive, 5 autosomal dominant [from 3 kindreds], and 10 sporadic) using direct automated sequencing. No
mutations were found in the autosomal recessive families. A point
mutation was identified in 1 of 3 autosomal dominant families, and a
base substitution was identified in 8 of 10 patients with the sporadic
form, though 1 was subsequently shown to be a low-frequency
polymorphism. These results suggest that mutations in ELA2
are not responsible for classical autosomal recessive Kostmann syndrome
but provide further evidence for the role of ELA2 in SCN.
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