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 vitro transcription/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. Am. J. Hematol. 83:789-794, 2008. V

A Pediatrician’s Practical Guide to Diagnosing and Treating Hereditary Spherocytosis in Neonates

“…[1][2][3][4][5] Numerous mutations in the genes encoding these membrane proteins have been described. Destruction of poorly deformable HS erythrocytes in the spleen is the primary cause of hemolysis in patients with HS.…”

“…[1][2][3][4][5] HS occurs worldwide and affects individuals from all racial and ethnic groups. Individual pediatricians encounter HS uncommonly, but hospitals and health care systems with large delivery services regularly deal with this condition, particularly in white neonates of northern European ancestry, in whom the condition can be as frequent as 1 in 1000 to 2000 births.…”

Ankyrin-1 gene exhibits allelic heterogeneity in conferring protection against malaria

“…However, as the result of extreme allelic heterogeneity of HS-causing genes, many alleles do not reach sufficient frequencies [55] or achieve consistent symptoms [56] to be easily associated with malaria protection. In addition, technical difficulties [29], confounding factors from large genetic variation in African populations [57], as well as poor diagnostics and health systems [57], pose significant challenges for dissecting the connection between HS and malaria. Furthermore, the varying allele frequency in African populations might introduce epistasis effects, possibly masking the genotype-phenotype associated typically observed in other populations [58].…”

“…HS is caused by mutations in ankyrin, spectrins, band 3 and protein 4.2, with ankyrin mutations contributing to more than 50% of all HS cases [23-27], where the severity depends greatly on the location and the nature of mutations [28]. However, the prevalence of HS in malaria endemic regions is not well studied; only isolated cases were reported [29-32]. Nevertheless, in vivo and in vitro studies have repeatedly suggested an association of HS with increased malaria resistance, and several mechanisms have been proposed, although not all of them were consistent [33-36].…”

A previously unrecognized Ankyrin‐1 mutation associated with Hereditary Spherocytosis in an Italian family

“…In most cases, ankyrin gene mutations are not only unique to individual kindreds but are also located throughout the coding exons and promoter region of the ankyrin gene. 5 To date, a total of 61 mutations are included in the HGMD public database. Small deletions and missense/nonsense mutations have been identified in approximately 70% of all mutations in the ANK1 gene.…”