A Large Deletion Within the Protein 4.1 Gene Associated With a Stable
Truncated mRNA and an Unaltered Tissue-Specific Alternative Splicing
N. Dalla Venezia,
P. Maillet,
L. Morlé,
L. Roda,
J. Delaunay, and
F. Baklouti
From CNRS URA 1171, Institut Pasteur de Lyon, Lyon, France; the
Centre Hospitalier Territorial, Papeete, Tahiti; and the Centre de
Génétique Moléculaire et Cellulaire,
Université Lyon, Villeurbanne, France.
Protein 4.1 is a major protein of the red blood cell skeleton. It
binds to the membrane through its 30-kD N-terminal domain and
to the spectrin-actin lattice through its 10-kD domain. We describe
here the molecular basis of a heterozygous hereditary elliptocytosis
(HE) associated with protein 4.1 partial deficiency. The responsible
allele displayed a greater than 70-kb genomic deletion, beginning
within intron 1 and ending within a 1.3-kb region upstream from exon
13. This deletion encompassed both erythroid and nonerythroid
translation initiation sites. It accounts for the largest deletion
known in genes encoding proteins of the red blood cell membrane.
The corresponding mRNA was shortened by 1727 bases, due to the absence
of exons 2 to 12. Nevertheless, this mRNA was stable. It showed a
similar pattern in lymphoblastoid cells as in reticulocytes.
Differential splicing of exons within the undeleted region remained
regulated in a tissue-specific manner. Exons 14, 15, and 17a were
absent from both reticulocyte and lymphocyte mRNAs, whereas exon 16 was
present in reticulocytes but absent from lymphocytes. Thus,
differential splicing on a local scale was not dependent on the overall
structure of protein 4.1 mRNA in this particular instance.
Blood, Vol. 91 No. 11 (June 1), 1998:
pp. 4361-4367
© 1998 by The American Society of Hematology.
