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Identification of three novel spectrin alpha I/74 mutations in hereditary
elliptocytosis: further support for a triple-stranded folding unit model of
the spectrin heterodimer contact site
N Parquet, I Devaux, L Boulanger, C Galand, P Boivin, MC Lecomte, D Dhermy and M Garbarz
INSERM U409, Genetique et Pathologie Moleculaires de L'Hematopoiese,
Faculte de Medecine X. Bicuat, Paris, France.
Six individuals with hereditary elliptocytosis (HE) or hereditary
pyropoikilocytosis (HPP) from three unrelated families were evaluated.
Defects in the ability of spectrin (Sp) to undergo self-association were
present, and associated with increased recovery of the Sp alpha I 74-kD
fragment after limited tryptic digestion (Sp alpha I/74 variant). Because
mutations associated with the Sp alpha I/74 variant described to date have
been localized to the 5' coding region of the alpha-Sp gene (exon 2) or at
the 3' coding end of the beta-Sp gene (exon 30), the polymerase chain
reaction (PCR)-based single-strand conformation polymorphism (SSCP) method
was used to detect mutations in these two regions. In one family with HE,
an abnormal pattern of migration of PCR- amplified fragments containing
exon 2 was observed, and led to the detection of a new mutation (Ile24Ser)
in helix 3 of repeating segment alpha 1. In the two other families, an
abnormal pattern of migration of PCR-amplified fragments containing exon 30
was observed in affected individuals, and sequencing led to the
identification of two new mutations (Ala2023Val and Trp2024Arg) in helix 1
of repeating segment beta 17. The elliptogenic potential of these mutations
emphasizes the importance of the conformational integrity of each of the
three helices involved in the formation of the Sp heterodimer contact site,
and will help identify critical amino acids involved in this interaction.
Volume 84,
Issue 1,
pp. 303-308,
07/01/1994
Copyright © 1994 by The American Society of Hematology
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