Mutations in the gene encoding neutrophil elastase in congenital and cyclic neutropenia

Congenital neutropenia and cyclic neutropenia are disorders of neutrophil p roduction predisposing patients to recurrent bacterial infections. Recently the locus for autosomal dominant cyclic neutropenia was mapped to chromoso me 19p13.3, and this disease is now attributable to mutations of the gene e ncoding neutrophil elastase (the ELA2 gene). The authors hypothesized that congenital neutropenia is also due to mutations of neutrophil elastase. Pat ients with congenital neutropenia, cyclic neutropenia, or Shwachman-Diamond syndrome were referred to the Severe Chronic Neutropenia International Reg istry. Referring physicians provided hematologic and clinical data. Mutatio nal analysis was performed by sequencing polymerase chain reaction (PCR)-am plified 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 w as; used to determine if the affected patients expressed both the normal an d the abnormal transcript. Twenty-two of 25 patients with congenital neutro penia had 18 different heterozygous mutations. Four of 4 patients with cycl ic neutropenia and 0 of 3 patients with Shwachman-Diamond syndrome had muta tions. For 5 patients with congenital neutropenia having mutations predicte d to alter RNA splicing or transcript structure, reverse transcriptase-PCR showed expression of both normal and abnormal transcripts. In cyclic neutro penia, the mutations appeared to cluster near the active site of the molecu le, whereas the opposite face was predominantly affected by the mutations f ound in congenital neutropenia. This study indicates that mutations of the gene encoding neutrophil elastase are probably the most common cause for se vere congenital neutropenia as well as the cause for sporadic and autosomal dominant cyclic neutropenia. (Blood. 2000;96:2317-2322) (C) 2000 by The Am erican Society of Hematology.