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This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Dekker, J. Articles by Roos, D. Search for Related Content PubMed PubMed Citation Articles by Dekker, J. Articles by Roos, D. Related Collections Red Cells Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  Blood, 15 February 2001, Vol. 97, No. 4, pp. 1106-1114 RED CELLS Seven new mutations in the nicotinamide adenine dinucleotide reduced-cytochrome b5 reductase gene leading to methemoglobinemia type I Jan Dekker, Michel H. M. Eppink, Rob van Zwieten, Thea de Rijk, Angel F. Remacha, Lap Kay Law, Albert M. Li, Kam Lau Cheung, Willem J. H. van Berkel, and Dirk Roos From the Central Laboratory of the Netherlands Blood Transfusion Service (CLB), and Laboratory for Experimental and Clinical Immunology, Academic Medical Center, University of Amsterdam, Amsterdam, and Department of Biomolecular Sciences, Laboratory of Biochemistry, Wageningen University, Wageningen, The Netherlands; Hospital de la Santa Creu I Sant Pau, Barcelona, Spain; Departments of Chemical Pathology and Paediatrics, Prince of Wales Hospital, Shatin, NT, Hong Kong. Cytochrome b5 reductase (b5R) deficiency manifests itself in 2 distinct ways. In methemoglobinemia type I, the patients only suffer from cyanosis, whereas in type II, the patients suffer in addition from severe mental retardation and neurologic impairment. Biochemical data indicate that this may be due to a difference in mutations, causing enzyme instability in type I and complete enzyme deficiency or enzyme inactivation in type II. We have investigated 7 families with methemoglobulinemia type I and found 7 novel mutations in the b5R gene. Six of these mutations predicted amino acid substitutions at sites not involved in reduced nicotinamide adenine dinucleotide (NADH) or flavin adenine dinucleotide (FAD) binding, as deduced from a 3-dimensional model of human b5R. This model was constructed from comparison with the known 3-dimensional structure of pig b5R. The seventh mutation was a splice site mutation leading to skipping of exon 5 in messenger RNA, present in heterozygous form in a patient together with a missense mutation on the other allele. Eight other amino acid substitutions, previously described to cause methemoglobinemia type I, were also situated in nonessential regions of the enzyme. In contrast, 2 other substitutions, known to cause the type II form of the disease, were found to directly affect the consensus FAD-binding site or indirectly influence NADH binding. Thus, these data support the idea that enzyme inactivation is a cause of the type II disease, whereas enzyme instability may lead to the type I form. © 2001 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: C. Ewenczyk, A. Leroux, A. Roubergue, V. Laugel, A. Afenjar, J. M. Saudubray, P. Beauvais, T. B. de Villemeur, M. Vidailhet, and E. Roze Recessive hereditary methaemoglobinaemia, type II: delineation of the clinical spectrum Brain, March 1, 2008; 131(3): 760 - 761. [Abstract] [Full Text] [PDF] M. J. Percy, M. J. S. Gillespie, G. Savage, A. E. Hughes, M. F. McMullin, and T. R. J. Lappin Familial idiopathic methemoglobinemia revisited: original cases reveal 2 novel mutations in NADH-cytochrome b5 reductase Blood, November 15, 2002; 100(10): 3447 - 3449. [Abstract] [Full Text] [PDF]

	Copyright © 2001 by American Society of Hematology         Online ISSN: 1528-0020