Ankyrin-linked hereditary spherocytosis in an African-American kindred.

Abstract

Mutations of ankyrin-1 are the most frequent cause of the inherited hemolytic anemia, hereditary spherocytosis (HS), in people of European ancestry. Ankyrin-1, which provides the primary linkage between the erythrocyte membrane skeleton and the plasma membrane, has numerous isoforms generated by alternative splicing, alternate polyadenylation, use of tissue-specific promoters, and alternate NH(2) or COOH-termini. Mutation detection in erythrocyte membrane protein genes, including ankyrin, has been a challenge, primarily due to the large size of these genes, and the apparent frequent occurrence of HS-associated null alleles. Using denaturing high-performance liquid chromatography (DHPLC), we screened the ankyrin gene of the proband of a large, three generation African-American kindred with ankyrin-deficient HS. DHPLC yielded an abnormal chromatogram for exon 1. Examination of the corresponding exon 1 sequence in genomic DNA from the proband revealed heterozygosity for a mutation of the initiator methionine (ATG to ATA Met 1 Ile). Coupled in vitrotranscription/translation studies with rabbit reticulocyte lysates demonstrated that the wild-type ankyrin erythroid cDNA initiates only from the known initiator methionine, indicating that the use of alternate initiator methionine is not a mechanism of isoform diversity in erythroid cells. The mutant ankyrin allele, unlike some initiator methionine mutations that utilize downstream codons for translation initiation, was associated with a null allele. This is the first report describing ankyrin-linked HS in an African-American kindred.

• Authors: Jose Sangerman, Yelena Maksimova, E Jennifer Edelman, Jon S Morrow, Bernard G Forget, Patrick G Gallagher
• Journal: American journal of hematology (Am J Hematol) Vol. 83 Issue 10 Pg. 789-94 (Oct 2008) ISSN: 1096-8652 [Electronic] United States
• PMID: 18704959 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright 2008 Wiley-Liss, Inc.

Chemical References

• Ankyrins
• Codon

Topics

• Black or African American (genetics)
• Alleles
• Ankyrins (deficiency, genetics)
• Base Sequence
• Case-Control Studies
• Chromatography, High Pressure Liquid
• Codon
• DNA Mutational Analysis
• Exons
• Family
• Female
• Gene Frequency
• Genetic Testing
• Heterozygote
• Humans
• Male
• Molecular Sequence Data
• Mutation
• Pedigree
• Siblings
• Spherocytosis, Hereditary (genetics)