Hereditary spherocytosis associated with deletion of human erythrocyte ankyrin gene on chromosome 8

Abstract

Hereditary spherocytosis (HS) is one of the most common hereditary haemolytic anaemias. HS red cells from both autosound dominant and recessive variants are spectrin-deficient, which correlates with the severity of the disease. Some patients with recessive HS have a mutation in the spectrin alpha-2 domain (S.L.M. et al., unpublished observations), and a few dominant HS patients have an unstable beta-spectrin that is easily oxidized, which damages the protein 4.1 binding site and weakens spectrin-actin interactions. In most patients, however, the cause of spectrin deficiency is unknown. The alpha- and beta-spectrin loci are on chromosomes 1 and 14 respectively. The only other genetic locus for HS is SPH2, on the short arm of chromosome 8 (8p11). This does not correspond to any of the known loci of genes for red cell membrane proteins including protein 4.1 (1p36.2-p34), the anion exchange protein (AE1, band 3; 17q21-qter), glycophorin C (2q14-q21), and beta-actin (7pter-q22). Human erythrocyte ankyrin, which links beta-spectrin to the anion exchange protein, has recently been cloned. We now show that the ankyrin gene maps to chromosome 8p11.2, and that one copy is missing from DNA of two unrelated children with severe HS and heterozygous deletions of chromosome 8 (del(8)(p11-p21.1)). Affected red cells are also ankyrin-deficient. The data suggest that defects or deficiency or ankyrin are responsible for HS at the SPH2 locus.

Analysis of genes and chromosomes by nonisotopic in situ hybridization

“…In contrast, the high efficiency of nonisotopic in situ hybridization with cloned genomic DNA fragments permits such an analysis not only on metaphase chromosomes, but also in interphase nuclei. The usefulness of this approach has been demonstrated for detecting a deletion of the ankyrin gene resulting in a subtype of hereditary spherocytosis [158] as well as for the demonstration of the carrier Status of women with deletions in the dystrophin gene [159]. Diagnostic applications for other genetic diseases including microdeletions, such as retinoblastoma, DiGeorge's Syndrome, or the 4p-minus Syndrome, can be predicted.…”

Translocation (8;21) in acute nonlymphocytic leukemia delineated by chromosomal in situ suppression hybridization

“…Painting of whole chromosomes using DNA libraries from sorted chromosomes provides the advantage that translocations involving any material from the painted chromosome can be detected. CISS hybridization of appropriate cosmid or YAC clones may be used for the identification of still smaller translocations, deletions, or inversions, as well as for the precise definition of breakpoints [11][12][13][14][15][16][17][18][19].…”

From anemia to cerebellar dysfunction

“…The subsequent assignment of the ANK-1 gene to chromosome 8 [32] suggested that abnormalities of ankyrin, might be important in a subset of HS patients. Ankyrin defects have now been described in a number of HS patients, including the recessive case mentioned above [60], a kindred with a deletion of chromosome 8 resulting in decreased dosage of the ANK-1 gene [26], and a large three-generation HS kindred where the ANK-1 gene was closely linked with the disorder [61]. Most of these cases are due to ankyrin deficiency resulting from aberrant transcription.…”

“…Ankyrin, is the major product of the ANK-1 gene locus which has been mapped to chromosome 8pll [26]. When proteins of the red cell membrane are separated by SDS/ PAGE, ankyrin, appears as a major polypeptide of 206 kDa followed by a ladder of minor ankyrin-related polypeptides, the principal having a molecular mass of 186 kDa [9].…”

“…The delayed onset of Purkinje cell neurodegeneration may result from partial compensation of function by one of the other members of the ankyrin gene family. The nb mouse may represent a model for neurological conditions associated with ankyrin, abnormalities, as spinal cord dysfunctions [62] and other neurological defects have been described in a small population of HS patients [26,571. However, these associated conditions may stem from the deletions of chromosome 8 observed in some of these cases.…”