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Erschienen in: Journal of Clinical Immunology 5/2015

01.07.2015 | Brief Communication

Mosaicism of an ELANE Mutation in an Asymptomatic Mother in a Familial Case of Cyclic Neutropenia

verfasst von: Osamu Hirata, Satoshi Okada, Miyuki Tsumura, Shuhei Karakawa, Itaru Matsumura, Yujiro Kimura, Toshiro Maihara, Shin’ichiro Yasunaga, Yoshihiro Takihara, Osamu Ohara, Masao Kobayashi

Erschienen in: Journal of Clinical Immunology | Ausgabe 5/2015

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Abstract

Purpose

To confirm and characterize mosaicism of the cyclic neutropenia (CyN)-related mutation in the ELANE gene identified in the asymptomatic mother of patients with CyN.

Methods

We identified sibling cases with CyN due to a novel heterozygous splicing site mutation, IVS4 +5SD G>T, in the ELANE gene, resulting in an internal in-frame deletion of 30 nucleotides (corresponding to a ten amino acid deletion, V161–F170). The mutated allele was also detected in their asymptomatic mother but at low frequency. We measured the frequency of the mutant allele from peripheral blood leukocytes (PBLs) by subcloning, and confirmed the allelic frequency of mosaicism in various cell types by massively parallel DNA sequencing (MPS) analysis.

Results

In the subcloning analysis, the mutant allele was identified in 21.36 % of PBLs from the asymptomatic mother, compared with 54.72 % of PBLs from the CyN patient. In the MPS analysis, the mutant allele was observed in approximately 30 % of mononuclear cells, CD3+ T cells, CD14+ monocytes and the buccal mucosa. Conversely, it was detected in low frequency in polymorphonuclear leukocytes (PLMLs) (3–4 %) and CD16+ granulocytes (2–3 %).

Conclusions

Mosaicism of the ELANE mutation has only previously been identified in one confirmed and one unconfirmed case of SCN. This is the first report of mosaicism of the ELANE mutation in a case of CyN. The MPS results suggest that this de novo mutation occurred during the two-cell stage of embryogenesis. PLMLs expressing the ELANE mutation were found to be actively undergoing apoptosis.
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Literatur
1.
2.
Zurück zum Zitat Palmer SE, Stephens K, Dale DC. Genetics, phenotype, and natural history of autosomal dominant cyclic hematopoiesis. Am J Med Genet. 1996;66:413–22.PubMedCrossRef Palmer SE, Stephens K, Dale DC. Genetics, phenotype, and natural history of autosomal dominant cyclic hematopoiesis. Am J Med Genet. 1996;66:413–22.PubMedCrossRef
3.
Zurück zum Zitat Dale DC, Person RE, Bolyard AA, Aprikyan AG, Bos C, Bonilla MA, et al. Mutations in the gene encoding neutrophil elastase in congenital and cyclic neutropenia. Blood. 2000;96:2317–22.PubMed Dale DC, Person RE, Bolyard AA, Aprikyan AG, Bos C, Bonilla MA, et al. Mutations in the gene encoding neutrophil elastase in congenital and cyclic neutropenia. Blood. 2000;96:2317–22.PubMed
4.
Zurück zum Zitat Horwitz M, Benson KF, Person RE, Aprikyan AG, Dale DC. Mutations in ELA2, encoding neutrophil elastase, define a 21-day biological clock in cyclic haematopoiesis. Nat Genet. 1999;23:433–6.PubMedCrossRef Horwitz M, Benson KF, Person RE, Aprikyan AG, Dale DC. Mutations in ELA2, encoding neutrophil elastase, define a 21-day biological clock in cyclic haematopoiesis. Nat Genet. 1999;23:433–6.PubMedCrossRef
5.
Zurück zum Zitat Horwitz MS, Duan Z, Korkmaz B, Lee HH, Mealiffe ME, Salipante SJ. Neutrophil elastase in cyclic and severe congenital neutropenia. Blood. 2007;109:1817–24.PubMedCentralPubMedCrossRef Horwitz MS, Duan Z, Korkmaz B, Lee HH, Mealiffe ME, Salipante SJ. Neutrophil elastase in cyclic and severe congenital neutropenia. Blood. 2007;109:1817–24.PubMedCentralPubMedCrossRef
6.
Zurück zum Zitat Bellanne-Chantelot C, Clauin S, Leblanc T, Cassinat B, Rodrigues-Lima F, Beaufils S, et al. Mutations in the ELA2 gene correlate with more severe expression of neutropenia: a study of 81 patients from the French Neutropenia Register. Blood. 2004;103:4119–25.PubMedCrossRef Bellanne-Chantelot C, Clauin S, Leblanc T, Cassinat B, Rodrigues-Lima F, Beaufils S, et al. Mutations in the ELA2 gene correlate with more severe expression of neutropenia: a study of 81 patients from the French Neutropenia Register. Blood. 2004;103:4119–25.PubMedCrossRef
7.
Zurück zum Zitat Schäffer AA, Klein C. Genetic heterogeneity in severe congenital neutropenia: how many aberrant pathways can kill a neutrophil? Curr Opin Allergy Clin Immunol. 2007;7:481–94.PubMedCentralPubMedCrossRef Schäffer AA, Klein C. Genetic heterogeneity in severe congenital neutropenia: how many aberrant pathways can kill a neutrophil? Curr Opin Allergy Clin Immunol. 2007;7:481–94.PubMedCentralPubMedCrossRef
8.
Zurück zum Zitat Ishikawa N, Okada S, Miki M, Shirao K, Kihara H, Tsumura M, et al. Neurodevelopmental abnormalities associated with severe congenital neutropenia due to the R86X mutation in the HAX1 gene. J Med Genet. 2008;45:802–7.PubMedCrossRef Ishikawa N, Okada S, Miki M, Shirao K, Kihara H, Tsumura M, et al. Neurodevelopmental abnormalities associated with severe congenital neutropenia due to the R86X mutation in the HAX1 gene. J Med Genet. 2008;45:802–7.PubMedCrossRef
9.
Zurück zum Zitat Sera Y, Kawaguchi H, Nakamura K, Sato T, Habara M, Okada S, et al. A comparison of the defective granulopoiesis in childhood cyclic neutropenia and in severe congenital neutropenia. Haematologica. 2005;90:1032–41.PubMed Sera Y, Kawaguchi H, Nakamura K, Sato T, Habara M, Okada S, et al. A comparison of the defective granulopoiesis in childhood cyclic neutropenia and in severe congenital neutropenia. Haematologica. 2005;90:1032–41.PubMed
10.
11.
Zurück zum Zitat Xia J, Bolyard AA, Rodger E, Stein S, Aprikyan AA, Dale DC, et al. Prevalence of mutations in ELANE, GFI1, HAX1, SBDS, WAS and G6PC3 in patients with severe congenital neutropenia. Br J Haematol. 2009;147:535–42.PubMedCentralPubMedCrossRef Xia J, Bolyard AA, Rodger E, Stein S, Aprikyan AA, Dale DC, et al. Prevalence of mutations in ELANE, GFI1, HAX1, SBDS, WAS and G6PC3 in patients with severe congenital neutropenia. Br J Haematol. 2009;147:535–42.PubMedCentralPubMedCrossRef
12.
Zurück zum Zitat Izawa K, Hijikata A, Tanaka N, Kawai T, Saito MK, Goldbach-Mansky R, et al. Detection of base substitution-type somatic mosaicism of the NLRP3 gene with >99.9 % statistical confidence by massively parallel sequencing. DNA Res. 2012;19:143–52.PubMedCentralPubMedCrossRef Izawa K, Hijikata A, Tanaka N, Kawai T, Saito MK, Goldbach-Mansky R, et al. Detection of base substitution-type somatic mosaicism of the NLRP3 gene with >99.9 % statistical confidence by massively parallel sequencing. DNA Res. 2012;19:143–52.PubMedCentralPubMedCrossRef
13.
Zurück zum Zitat Flaherty P, Natsoulis G, Muralidharan O, Winters M, Buenrostro J, Bell J, et al. Ultrasensitive detection of rare mutations using next-generation targeted resequencing. Nucleic Acids Res. 2012;40:e2.PubMedCentralPubMedCrossRef Flaherty P, Natsoulis G, Muralidharan O, Winters M, Buenrostro J, Bell J, et al. Ultrasensitive detection of rare mutations using next-generation targeted resequencing. Nucleic Acids Res. 2012;40:e2.PubMedCentralPubMedCrossRef
14.
Zurück zum Zitat Ancliff PJ, Gale RE, Watts MJ, Liesner R, Hann IM, Strobel S, et al. Paternal mosaicism proves the pathogenic nature of mutations in neutrophil elastase in severe congenital neutropenia. Blood. 2002;100:707–9.PubMedCrossRef Ancliff PJ, Gale RE, Watts MJ, Liesner R, Hann IM, Strobel S, et al. Paternal mosaicism proves the pathogenic nature of mutations in neutrophil elastase in severe congenital neutropenia. Blood. 2002;100:707–9.PubMedCrossRef
15.
Zurück zum Zitat Benson KF, Horwitz M. Possibility of somatic mosaicism of ELA2 mutation overlooked in an asymptomatic father transmitting severe congenital neutropenia to two offspring. Br J Haematol. 2002;118:923. author reply923–4.PubMed Benson KF, Horwitz M. Possibility of somatic mosaicism of ELA2 mutation overlooked in an asymptomatic father transmitting severe congenital neutropenia to two offspring. Br J Haematol. 2002;118:923. author reply923–4.PubMed
16.
Zurück zum Zitat Germeshausen M, Schulze H, Ballmaier M, Zeidler C, Welte K. Mutations in the gene encoding neutrophil elastase (ELA2) are not sufficient to cause the phenotype of congenital neutropenia. Br J Haematol. 2001;115:222–4.PubMedCrossRef Germeshausen M, Schulze H, Ballmaier M, Zeidler C, Welte K. Mutations in the gene encoding neutrophil elastase (ELA2) are not sufficient to cause the phenotype of congenital neutropenia. Br J Haematol. 2001;115:222–4.PubMedCrossRef
17.
Zurück zum Zitat Grenda DS, Murakami M, Ghatak J, Xia J, Boxer LA, Dale D, et al. Mutations of the ELA2 gene found in patients with severe congenital neutropenia induce the unfolded protein response and cellular apoptosis. Blood. 2007;110:4179–87.PubMedCentralPubMedCrossRef Grenda DS, Murakami M, Ghatak J, Xia J, Boxer LA, Dale D, et al. Mutations of the ELA2 gene found in patients with severe congenital neutropenia induce the unfolded protein response and cellular apoptosis. Blood. 2007;110:4179–87.PubMedCentralPubMedCrossRef
18.
Zurück zum Zitat Klein C. Genetic defects in severe congenital neutropenia: emerging insights into life and death of human neutrophil granulocytes. Annu Rev Immunol. 2011;29:399–413.PubMedCrossRef Klein C. Genetic defects in severe congenital neutropenia: emerging insights into life and death of human neutrophil granulocytes. Annu Rev Immunol. 2011;29:399–413.PubMedCrossRef
19.
Zurück zum Zitat Köllner I, Sodeik B, Schreek S, Heyn H, von Neuhoff N, Germeshausen M, et al. Mutations in neutrophil elastase causing congenital neutropenia lead to cytoplasmic protein accumulation and induction of the unfolded protein response. Blood. 2006;108:493–500.PubMedCrossRef Köllner I, Sodeik B, Schreek S, Heyn H, von Neuhoff N, Germeshausen M, et al. Mutations in neutrophil elastase causing congenital neutropenia lead to cytoplasmic protein accumulation and induction of the unfolded protein response. Blood. 2006;108:493–500.PubMedCrossRef
Metadaten
Titel
Mosaicism of an ELANE Mutation in an Asymptomatic Mother in a Familial Case of Cyclic Neutropenia
verfasst von
Osamu Hirata
Satoshi Okada
Miyuki Tsumura
Shuhei Karakawa
Itaru Matsumura
Yujiro Kimura
Toshiro Maihara
Shin’ichiro Yasunaga
Yoshihiro Takihara
Osamu Ohara
Masao Kobayashi
Publikationsdatum
01.07.2015
Verlag
Springer US
Erschienen in
Journal of Clinical Immunology / Ausgabe 5/2015
Print ISSN: 0271-9142
Elektronische ISSN: 1573-2592
DOI
https://doi.org/10.1007/s10875-015-0165-1

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