Ankyrin Bugey: A de novo deletional frameshift variant in exon 6 of the ankyrin gene associated with spherocytosis

Abstract

We describe a case of spherocytosis in a French child splenectomized at age 10 years. The parents were devoid of any clinical, hematological, or biochemical abnormalities. Following splenectomy, the proposita exhibited a reduction of red cell membrane ankyrin. The variable number of dinucleotide repeats associated with the erythroid ankyrin gene (ANK1) were studied at the genomic level. The father, the mother, and the proposita had the AC 14 /AC 11 , AC 14 /AC 14 , and AC 14 /AC 11 genotypes, respectively, although the proposita exhibited a pattern consistent with an AC 14 ,-combination at the cDNA level. We thought there could be a de novo mutation in the ANK1 allele of paternal origin (AC 11 ). A false paternity seemed most unlikely. Based on PCR-amplification of exons, SSCP analysis, and, when appropriate, nucleotide sequencing, we found a one-nucleotide deletion in codon 146 (exon 6): 521delC, ACG→AG. This placed in phase a TAG triplet normally overlapping codons 150 and 151. Early interruption of translation presumably accounted for the premature degradation of mutant mRNA. Restriction analysis confirmed the presence of the mutation in the proposita and its absence in the parents. The variant was designated ankyrin Bugey. Am.

Mutational characteristics of ANK1 and SPTB genes in hereditary spherocytosis

“…After a literature search related to HS, 50 cases including 31 ANK1 and 19 SPTB mutations were identified. These reports provided laboratory and clinical data, such as Hb level, splenectomy, and aplastic crisis which allowed calculation of the difference of Hb level according to mutated genes or the frequencies of splenectomy and aplastic crisis according to located domain of mutation in each gene.…”

Red blood cell membrane disorders

“…These are nonsense or frameshift mutations that result in either unstable ankyrin mRNA transcripts or truncated peptides. Mutant ankyrins Bari, Bugey, Duisburg, Einbeck, Marburg, Napoli I, Osterholz and Stuttgart are truncated in the band 3 binding domain (Eber et al , 1996; Miraglia del Giudice et al , 1996; Morlé et al , 1997; Randon et al , 1997), ankyrins Anzio, Napoli II and Porta Westfalica are affected in the spectrin binding domain, and ankyrins Bovenden and Saint‐Etienne 1 and 2 have premature termination within the regulatory domain (Eber et al , 1996; Hayette et al , 1998). In ankyrin Rakovnik a nonsense mutation within the regulatory domain leads to a selective deficiency of the major ankyrin isoform, protein 2.1 (Jarolim et al , 1995b).…”

“…HS patients with ankyrin defects have prominent spherocytosis without other morphological defects. Haemolysis and anaemia vary from mild to severe (Eber et al , 1996; Miraglia del Giudice et al , 1996, 1998a; Morlè et al , 1997; Randon et al , 1997; Hayette et al , 1998). In general, patients with dominant defects are less affected than those with recessive mutations; however, there is considerable overlap.…”

Low frequency of ankyrin mutations in hereditary spherocytosis: Identification of three novel mutations

“…Several mutations of the ankyrin-1 gene (ANK1; MIM# 182900) have been described in the last few years (Jarolim P, et al 1995;Del Giudice EM, et al 1996;Eber SW, et al 1996;Gallagher PG & Forget BG. Dominant HS is primarily associated with null phenotypes caused by nonsense or frameshift mutations, whereas recessive HS might be caused by missense or promoter mutations (Del Giudice EM, et al 1996;Eber SW, et al 1996; Morle L, et al 1997;Randon J, et al 1997;Del Giudice EM, et al 1998;Hayette S, et al 1998;Yawata Y, et al 2000), even though most of these 'recessive ' HS are, probably, de novo mutations (Del Giudice EM, et al 1996;Eber SW, et al 1996;Morle L, et al 1997;Del Giudice EM, et al 1998) which have just occurred in the proband. Dominant HS is primarily associated with null phenotypes caused by nonsense or frameshift mutations, whereas recessive HS might be caused by missense or promoter mutations (Del Giudice EM, et al 1996;Eber SW, et al 1996; Morle L, et al 1997;Randon J, et al 1997;Del Giudice EM, et al 1998;Hayette S, et al 1998;Yawata Y, et al 2000), even though most of these 'recessive ' HS are, probably, de novo mutations (Del Giudice EM, et al 1996;Eber SW, et al 1996;Morle L, et al 1997;Del Giudice EM, et al 1998) which have just occurred in the proband.…”