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Research Article Free access | 10.1172/JCI116203

An isoform-specific mutation in the protein 4.1 gene results in hereditary elliptocytosis and complete deficiency of protein 4.1 in erythrocytes but not in nonerythroid cells.

J G Conboy, J A Chasis, R Winardi, G Tchernia, Y W Kan, and N Mohandas

Cell and Molecular Biology Division, Lawrence Berkeley Laboratory, University of California, Berkeley 94720.

Find articles by Conboy, J. in: PubMed | Google Scholar

Cell and Molecular Biology Division, Lawrence Berkeley Laboratory, University of California, Berkeley 94720.

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Cell and Molecular Biology Division, Lawrence Berkeley Laboratory, University of California, Berkeley 94720.

Find articles by Winardi, R. in: PubMed | Google Scholar

Cell and Molecular Biology Division, Lawrence Berkeley Laboratory, University of California, Berkeley 94720.

Find articles by Tchernia, G. in: PubMed | Google Scholar

Cell and Molecular Biology Division, Lawrence Berkeley Laboratory, University of California, Berkeley 94720.

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Cell and Molecular Biology Division, Lawrence Berkeley Laboratory, University of California, Berkeley 94720.

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Published January 1, 1993 - More info

Published in Volume 91, Issue 1 on January 1, 1993
J Clin Invest. 1993;91(1):77–82. https://doi.org/10.1172/JCI116203.
© 1993 The American Society for Clinical Investigation
Published January 1, 1993 - Version history
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Abstract

Multiple protein 4.1 isoforms are expressed in a variety of tissues through complex alternative pre-mRNA splicing events, one function of which is to regulate use of two alternative translation initiation signals. Late erythroid cells express mainly the downstream initiation site for synthesis of prototypical 80-kD isoforms; nonerythroid cells in addition use an upstream site to encode higher molecular mass isoform(s). In this study, we examined the effects of a 5' gene rearrangement in a family with hereditary elliptocytosis and complete deficiency of erythrocyte 4.1 protein on 4.1 isoform expression in erythroid vs. nonerythroid cells. Patient 4.1 mRNAs from reticulocytes, fibroblasts, and B lymphocytes were amplified by reverse transcriptase/polymerase chain reaction techniques and shown to exhibit a 318-nucleotide deletion that encompasses the downstream AUG, but leaves intact the upstream AUG. Immunoblot analysis revealed a total deficiency of 4.1 in patient red cells and a selective deficiency of 80-kD isoform(s) but not high molecular weight 4.1 in patient nonerythroid cells. Thus, the 4.1 gene mutation in this family produces an isoform-specific deficiency that is manifested clinically in tissue-specific fashion, such that red cells are affected but other cell types are unaffected because of tissue-specific differences in RNA splicing and translation initiation.

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