|
|
 Previous Article | Table of Contents | Next Article 
Biochemical and Molecular Characterization of Hereditary Myeloperoxidase Deficiency
Maurizio Romano,
Pietro Dri,
Liviana Dadalt,
Pierluigi Patriarca, and
Francisco E. Baralle
From the International Centre for Genetic Engineering and Biotechnology, Trieste, Italy; Dipartimento di Fisiologia e Patologia, Università di Trieste, Trieste, Italy; and the Dipartimento di Pediatria, Padova, Italy.
Hereditary myeloperoxidase (MPO) deficiency is a neutrophil disorder characterized by the lack of peroxidase activity. Cytochemical, biochemical, spectroscopic, immunocytochemical, and genetic studies were carried out on a 5-year-old MPO-deficient subject and on her parents. The father was also MPO-deficient, whereas the mother had 24% of normal MPO activity. Although the typical absorption spectrum of MPO was absent in both the father and daughter, the father's neutrophils, and not those of the daughter, contained material antigenically related to MPO. In the MPO gene of the father, two mutations were found, each located in a different allele: a T  C transition, causing the nonconservative replacement M251T and a 14-base deletion within exon 9. The M251T substitution occurred in the carboxy-terminal region of the light chain that is included in the heme pocket. The daughter inherited the 14-base deletion from her father. The study of the MPO mRNAs present in liquid cultures of granulocyte precursors surprisingly showed that the same genetic defect, ie, the 14-base deletion, seemed to exhibit different mRNA phenotypes in the father and the daughter. In fact, mRNA derived from the 14-base-deleted allele was not found in the father and an aberrantly spliced MPO mRNA with a 77-base deletion of exon 9, which includes the 14-base deletion and leads to the generation of a premature stop codon, was found in the daughter. The possibility that  77 mRNA could derive from other mutations linked to the 14 allele was dismissed because no sequence differences were found in the region (exons and exon-intron junctions). Our data indicate that the alteration of the mRNA context caused by the 14-base deletion provide a basis for the 77-base deletion in the mRNA processing. Since the granulocyte precursors from the liquid cultures of the father were more differentiated than those from the daughter, the observed different behavior of the 14-base-deleted allele in the father and daughter may be the result of a differentiation-stage dependent control of altered spliced mRNA, which may be tolerated during the early stages of differentiation but degraded at later stages. In the liquid cultures of the daughter's cells, in addition to the mRNA with the 77-base deletion, a mRNA with the wild type sequence was also found. This mRNA was inherited from the mother, since no mutations were found in her MPO cDNA and MPO gene. The MPO defect might be caused by a regulatory mutation that induces the MPO gene switch off at an early stage of granulocyte differentiation.
Blood, Vol. 90 No. 10 (November 15), 1997:
pp. 4126-4134
© 1997 by The American Society of Hematology.
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
This article has been cited by other articles:
|
|
|
|
 
G P Spickett
Immune deficiency disorders involving neutrophils
J. Clin. Pathol.,
September 1, 2008;
61(9):
1001 - 1005.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Y. Yu, Y. Su, S. R. Opalenik, T. Sobolik-Delmaire, N. F. Neel, S. Zaja-Milatovic, S. T. Short, J. Sai, and A. Richmond
Short tail with skin lesion phenotype occurs in transgenic mice with keratin-14 promoter-directed expression of mutant CXCR2
J. Leukoc. Biol.,
August 1, 2008;
84(2):
406 - 419.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. Reumaux, M. de Boer, A. B. Meijer, P. Duthilleul, and D. Roos
Expression of myeloperoxidase (MPO) by neutrophils is necessary for their activation by anti-neutrophil cytoplasm autoantibodies (ANCA) against MPO
J. Leukoc. Biol.,
June 1, 2003;
73(6):
841 - 849.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
I. Cascorbi, S. Henning, J. Brockmöller, J. Gephart, C. Meisel, J. M. Müller, R. Loddenkemper, and I. Roots
Substantially Reduced Risk of Cancer of the Aerodigestive Tract in Subjects with Variant -463A of the Myeloperoxidase Gene
Cancer Res.,
February 1, 2000;
60(3):
644 - 649.
[Abstract]
[Full Text]
|
|
|
|
|
|
|
Y. Aratani, H. Koyama, S.-i. Nyui, K. Suzuki, F. Kura, and N. Maeda
Severe Impairment in Early Host Defense against Candida albicans in Mice Deficient in Myeloperoxidase
Infect. Immun.,
April 1, 1999;
67(4):
1828 - 1836.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
