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Amino‐acid substitution in α‐spectrin commonly coinherited with nondominant hereditary spherocytosis
Author(s) -
Tse William T.,
Gallagher Patrick G.,
Jenkins Patricia B.,
Wang Yongping,
Benoit Lori,
Speicher David,
Winkelmann John C.,
Agre Peter,
Forget Bernard G.,
Marchesi Sally L.
Publication year - 1997
Publication title -
american journal of hematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.456
H-Index - 105
eISSN - 1096-8652
pISSN - 0361-8609
DOI - 10.1002/(sici)1096-8652(199703)54:3<233::aid-ajh10>3.0.co;2-e
Subject(s) - spectrin , hereditary spherocytosis , point mutation , spherocytosis , allele , genetics , hemolytic anemia , microbiology and biotechnology , mutation , biology , compound heterozygosity , gene , chemistry , biochemistry , immunology , splenectomy , spleen , cytoskeleton , cell
Nondominant hereditary spherocytosis (ndHS) is a disorder characterized in some patients by severe hemolytic anemia and marked deficiency of erythrocyte spectrin. This report describes the identification of a variant spectrin chain, α‐spectrin Bughill or α BH , that is associated with this disorder in a number of patients. Tryptic maps of spectrin from affected individuals revealed an acidic shift in isoelectric point of the αll domain peptides at 46 kD and 35 kD. A point mutation at codon 970 of the α‐spectrin gene (GCT→GAT), that changes the encoded amino acid from an alanine to an aspartic acid, was identified in genomic DNA of affected patients. The α BH variant was present in 8 patients with ndHS from five different kindreds but was absent in 4 patients from two other kindreds. The 8 ndHS patients with the α BH variant appeared to be homozygous for the α BH variant by analysis of peptide maps of limited tryptic digests of erythrocyte spectrin. However, following genomic DNA analysis, only 2 of these patients were true homozygotes, whereas 6 were found to be doubly heterozygous for the α BH allele and a second, presumably abnormal, α‐spectrin gene. These results suggest that, in these 6 patients, the second α‐spectrin allele is in fact associated with one or more genetic defect(s), causing decreased accumulation of α‐spectrin. The pattern of transmission of the α BH allele in certain families suggests that the α BH amino‐acid substitution is not itself responsible for ndHS but is more likely a polymorphic variant that, in some but not all cases, is in linkage disequilibrium with another uncharacterized α‐spectrin gene defect that itself is a cause of ndHS. Am. J. Hematol. 54:233–241, 1997 © 1997 Wiley‐Liss, Inc.