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

Congenital neutropenia and cyclic neu-tropenia are disorders of neutrophil pro-duction predisposing patients to recur-rent bacterial infections. Recently the locus for autosomal dominant cyclic neutropenia was mapped to chromo-some 19p13.3, and this disease is now attrib-utable to mutations of the gene encoding neutrophil elastase (the ELA2 gene). The authors hypothesized that congenital neu-tropenia is also due to mutations of neutro-phil elastase. Patients with congenital neu-tropenia, cyclic neutropenia, or Shwachman-Diamond syndrome were referred to the Severe Chronic Neutropenia International Registry. Referring physicians provided he-matologic and clinical data. Mutational anal-ysis was performed by sequencing polymer-ase chain reaction (PCR)-amplified genomic DNA for each of the 5 exons of the neutro-phil ELA2 gene and 20 bases of the flanking regions. RNA from bone marrow mono-nuclear 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 syn-drome 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 ab-normal transcripts. In cyclic neutropenia, the mutations appeared to cluster near the active site of the molecule, whereas the op-posite face was predominantly affected by the mutations found in congenital neutro-penia. 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 dom-inant cyclic neutropenia. (Blood. 2000;96