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Blood, 15 December 2005, Vol. 106, No. 13, pp. 4367-4369. Prepublished online as a Blood First Edition Paper on September 8, 2005; DOI 10.1182/blood-2005-05-1813. This Article Full Text (PDF) All Versions of this Article: 2005-05-1813v1 106/13/4367    most recent Alert me when this article is cited Alert me if a correction is posted 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 Costa, D. B Articles by Forget, B. G Search for Related Content PubMed PubMed Citation Articles by Costa, D. B Articles by Forget, B. G Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted May 4, 2005 Accepted June 24, 2005 A novel splicing mutation of the -spectrin gene in the original hereditary pyropoikilocytosis kindred Daniel B Costa, Larisa Lozovatsky, Patrick G Gallagher, and Bernard G Forget* Department of Medicine, Yale University School of Medicine, New Haven, CT, USA Departmernt of Pediatrics, Yale University School of Medicine, New Haven, CT, USA * Corresponding author; email: bernard.forget{at}yale.edu. Hereditary pyropoikilocytosis (HPP) is a severe hemolytic anemia due to abnormalities of the RBC membrane skeleton, first reported in 1975 by Zarkowsky et al. In the original HPP kindred, the disease has been known to be due to compound heterozygosity for an allele encoding a structural variant of -spectrin (L207P) and a -spectrin allele associated with a defect in a-spectrin production. The molecular basis of this production defective allele has been unknown. To identify the molecular basis of this mutant allele, an RT-PCR approach was utilized to examine -spectrin cDNA in reticulocyte RNA obtained from one of the original HPP patients described by Zarkowsky et al. In transcripts from the production-defective, non-L207P allele, a pattern of abnormal splicing between exon 22 and 23 was identified, resulting in insertion of intronic fragments with an in-frame premature termination codon. In corresponding genomic DNA, a G to A substitution at position +5 of the donor consensus splice site of IVS 22 was found. Heterozygosity for this mutation was confirmed in genomic DNA of the HPP siblings and their asymptomatic mother. Following gene transfer into tissue culture cells, there was complete absence of normally spliced -spectrin gene transcripts derived from a minigene containing the IVS 22 +5 mutation. The identification of this mutant -spectrin allele associated with a defect in -spectrin production completes the characterization of the molecular defects in the original HPP family reported 30 years ago. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: A cell by any other name Narla Mohandas Blood 2005 106: 4017. [Full Text] [PDF] This article has been cited by other articles: W. Tolpinrud, Y. D. Maksimova, B. G. Forget, and P. G. Gallagher Nonsense mutations of the {alpha}-spectrin gene in hereditary pyropoikilocytosis Haematologica, November 1, 2008; 93(11): 1752 - 1754. [Full Text] [PDF] X. Pei, X. Guo, R. Coppel, S. Bhattacharjee, K. Haldar, W. Gratzer, N. Mohandas, and X. An The ring-infected erythrocyte surface antigen (RESA) of Plasmodium falciparum stabilizes spectrin tetramers and suppresses further invasion Blood, August 1, 2007; 110(3): 1036 - 1042. [Abstract] [Full Text] [PDF]

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