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      Severe congenital neutropenia in a multigenerational family with a novel neutrophil elastase ( ELANE) mutation

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          Abstract

          We have analysed a family with nine congenital neutropenia patients in four generations, several of which we have studied in a long-term follow-up of over 25 years. The patients were mild to severe neutropenic and suffered from various recurrent bacterial infections. Mutations in the genes ELANE, CSF3R and GFI1 have been reported in patients with autosomal dominant congenital neutropenias. Using a small-scale linkage analysis with markers around the ELANE, CSF3R, CSF3 and GFI1 genes, we were able to determine that the disease segregated with markers around the ELANE gene. We identified a novel mutation in the ELANE gene in all of the affected family members that was not present in any of the healthy family members. The mutation leads to an A28S missense mutation in the mature protein. None of these patients developed leukaemia. This is the first truly multigenerational family with mutations in ELANE as unambiguous cause of severe congenital neutropenia SCN.

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          Nomenclature for the description of human sequence variations.

          Johan T. den Dunnen, Emmanuel Antonarakis (2001)
          A nomenclature system has recently been suggested for the description of changes (mutations and polymorphisms) in DNA and protein sequences. These nomenclature recommendations have now been largely accepted. However, current rules do not yet cover all types of mutations, nor do they cover more complex mutations. This document lists the existing recommendations and summarizes suggestions for the description of additional, more complex changes. Another version of this paper has been published in Hum Mut 15:7-12, 2000.
          Article 0 comments Cited 139 times – based on 0 reviews     Review now
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            Mutations in the gene encoding neutrophil elastase in congenital and cyclic neutropenia.

            G Kannourakis, K Welte, Adam L Boxer … (2000)
            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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              Mutations in the gene for the granulocyte colony-stimulating-factor receptor in patients with acute myeloid leukemia preceded by severe congenital neutropenia.

              B. Löwenberg, F. Dong-A-Zok, N Tidow … (1995)
              In severe congenital neutropenia the maturation of myeloid progenitor cells is arrested. The myelodysplastic syndrome and acute myeloid leukemia develop in some patients with severe congenital neutropenia. Abnormalities in the signal-transduction pathways for granulocyte colony-stimulating factor (G-CSF) may play a part in the progression to acute myeloid leukemia. We isolated genomic DNA and RNA from hematopoietic cells obtained from two patients with acute myeloid leukemia and histories of severe congenital neutropenia. The nucleotide sequences encoding the cytoplasmic domain of the G-CSF receptor were amplified by means of the polymerase chain reaction and sequenced. Murine myeloid 32D.C10 cells were transfected with complementary DNA encoding the wild-type or mutant G-CSF receptors and tested for their responses to G-CSF. Point mutations in the gene for the G-CSF receptor were identified in both patients. The mutations, a substitution of thymine for cytosine at the codon for glutamine at position 718 (Gln718) in one patient and at the codon for glutamine at position 731(Gln731) in the other, caused a truncation of the C-terminal cytoplasmic region of the receptor. Both mutant and wild-type genes for the G-CSF receptor were present in leukemic cells from the two patients. In one patient, the mutation was also found in the neutropenic stage, before the progression to acute myeloid leukemia. The 32D.C10 cells expressing mutant receptors had abnormally high proliferative responses but failed to mature when cultured in G-CSF. The mutant G-CSF receptors also interfered with terminal maturation mediated by the wild-type G-CSF receptor in the 32D.C10 cells that coexpressed the wild-type and mutant receptors. Mutations in the gene for the G-CSF receptor that interrupt signals required for the maturation of myeloid cells are involved in the pathogenesis of severe congenital neutropenia and associated with the progression to acute myeloid leukemia.
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                Author and article information

                Contributors
                : +31-71-5261784 , +31-71-5266758 , E.van_de_Vosse@LUMC.nl
                Journal
                Journal ID (nlm-ta): Ann Hematol
                Title: Annals of Hematology
                Publisher: Springer-Verlag (Berlin/Heidelberg )
                ISSN (Print): 0939-5555
                ISSN (Electronic): 1432-0584
                Publication date (Electronic): 28 August 2010
                Publication date PMC-release: 28 August 2010
                Publication date (Print): February 2011
                Volume: 90
                Issue: 2
                Pages: 151-158
                Affiliations
                [1 ]Department of Infectious Diseases, C5-P, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands
                [2 ]Emma Children’s Hospital, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
                [3 ]Department of Pulmonology, Leiden University Medical Center, Leiden, The Netherlands
                Article
                Publisher ID: 1056
                DOI: 10.1007/s00277-010-1056-4
                PMC ID: 3018258
                PubMed ID: 20803142
                SO-VID: 5fddf4d8-4a24-4cbe-ae71-83cc647a8bc1
                Copyright © © The Author(s) 2010
                History
                Date received : 2 August 2010
                Date accepted : 16 August 2010
                Categories
                Subject: Original Article
                Custom metadata
                issue-copyright-statement © Springer-Verlag 2011

                ScienceOpen disciplines: Hematology
                Keywords: neutrophil elastase,ela2,elane,mutation,severe congenital neutropenia
                Data availability:
                ScienceOpen disciplines: Hematology
                Keywords: neutrophil elastase, ela2, elane, mutation, severe congenital neutropenia

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