Other entities represented in this entry:
HGNC Approved Gene Symbol:ANK1
Cytogenetic location:8p11.21 Genomic coordinates(GRCh38) :8:41,653,225-41,896,741 (from NCBI)
By analysis of cDNA for human erythroid ankyrin,Lux et al. (1990) determined that the mature protein contains 1,880 amino acids comprising an N-terminal domain binding integral membrane proteins and tubulin, a central domain binding spectrin and vimentin, and an acidic C-terminal 'regulatory' domain containing an alternatively spliced sequence missing from ankyrin variant 2.2. The N-terminal domain is composed almost entirely of 22 tandem 33-amino acid repeats.
Lambert et al. (1990) found that the cDNA sequence has a large open reading frame of 5,636 basepairs coding for a polypeptide of 1,879 amino acids for the predicted molecular mass of 206 kD. Ankyrin comprises a band-3 (SLC4A1;109270)-binding domain, a spectrin-binding domain, and a regulatory domain. The band-3-binding domain consists of 23 homologous repeats, each 33 amino acids in length. The regulatory domain differs in length in the 2 isoforms of ankyrin, proteins 2.1 and 2.2.
By Northern blot analysis of human skeletal muscle tissue with an erythroid ANK1 probe,Gallagher and Forget (1998) detected expression of 2.3- and 1.6-kb transcripts, much smaller than the 7.3- and 9.0-kb transcripts observed in erythroid tissue RNA. Using a 5-prime RACE skeletal muscle product as probe, they identified a cDNA encoding a 155-amino acid protein. Secondary structure analysis predicted the presence of a highly charged N-terminal domain followed by a C-terminal domain composed of alternating alpha helix and beta sheet. The membrane-binding domain, the spectrin/fodrin-binding domain, and most of the regulatory domains found in the erythroid form of ANK1 are missing. Genomic sequence analysis determined that the smaller transcript contains 4 exons, a novel exon 1 followed by the erythroid exons 40, 41, and 42, spread over approximately 10 kb. Exon 1 is located in intron 39 of the erythroid ANK gene. Northern blot analysis revealed abundant expression of the 2.3- and 1.6-kb transcripts restricted to skeletal and cardiac muscle with lesser amounts of 3.7- and 7.0-kb transcripts. Immunoblot analysis showed that muscle ANK1 is readily detected as 28- and 30-kD proteins in skeletal muscle but that detection of 70-kD and 210-kD proteins in erythrocyte membranes requires prolonged exposure.
Tse et al. (1990) described the structure of the ANK1 gene corresponding to the domain structure of the protein.
By fluorescence-based in situ hybridization,Tse et al. (1990) localized the ankyrin gene to chromosome 8p11.2.Lux et al. (1990) independently reported localization of ANK1 to chromosome 8p11.2 by FISH analysis.
Using a yeast-2-hybrid screen,Lange et al. (2012) found that the obscurin (OBSCN;608616)-interacting isoform of human ankyrin-1, sANK1.5, also interacted with human KCTD6 (618791) in striated muscle. Obscurin-binding domain-2 of sANK1.5 interacted with the N-terminal BTB/POZ domain of KCTD6. The interaction was promoted by acetylation of sANK1.5 C-terminal lysines, and subsequent sANK1.5 protein turnover depended on KCTD6-associated neddylation and ubiquitylation, as well as the oligomerization state of the protein. KCTD6 was upregulated during muscle development and mediated association of sANK1.5 with cullin-3 (CUL3;603136), thereby regulating turnover of sANK1.5. Characterization of KCTD6 binding revealed that KCTD6 formed parallel homotetramers. The N-terminal BTB/POZ domain of KCTD6 was important for initial dimerization, whereas its C terminus was important for complete tetramerization and regulation of its interaction with CUL3 substrate proteins. Regulation of cullin-dependent sANK1.5 turnover depended on the presence of obscurin, as obscurin-knockout mouse muscle displayed reduced sAnk1.5 levels and mislocalization of the sAnk1.5/Kctd6 complex.
Davies and Lux (1989) stated that dosage analysis in 2 hereditary spherocytosis patients with chromosome 8p11 deletions showed them to be hemizygous for the ankyrin gene. A corresponding reduction of approximately 50% in the amount of ankyrin protein was also seen in these patients, who had mental retardation in addition to the red cell defect. In both normoblastosis mice and hereditary spherocytosis humans, spectrin is also reduced as a secondary phenomenon.
Eber et al. (1996) screened all 42 coding exons plus the 5-prime untranslated/promoter region of ankyrin-1 and the 19 coding exons of band 3 (SLC4A1;109270) in 46 hereditary spherocytosis families. They identified 12 ankyrin-1 mutations and 5 band-3 mutations. Missense mutations and a mutation in the putative ankyrin-1 promoter were stated to be common in recessive HS (see612641.0002). In contrast, ankyrin-1 and band 3 frameshift and nonsense null mutations prevailed in dominant HS. Increased accumulation of the normal protein product partially compensated for the ankyrin-1 or band 3 defects in some of these null mutations. The findings indicated toEber et al. (1996) that ankyrin-1 mutations are a major cause of dominant and recessive HS (between 35 and 65%), that band 3 mutations are less common (between 15 and 25%), and that the severity of HS is modified by factors other than the primary gene defect.
In the proband reported byDuru et al. (1992),Edelman et al. (2007) identified a homozygous splice site mutation in the ANK1 gene (612641.0007). Each parent was heterozygous for the mutation.
Mice with normoblastosis (nb/nb) have a deficiency of ankyrin. The nb locus maps to mouse chromosome 8 in a segment that shows homology of synteny with human 8p (White and Barker, 1987).White et al. (1990) used immunologic and biochemical methods to demonstrate an altered (150 kD) immunoreactive ankyrin in homozygous (nb/nb) and heterozygous (nb/+) reticulocytes.
Mice deficient in ankyrin have, in addition to hemolytic anemia, significant neurologic dysfunction associated with Purkinje cell degeneration in the cerebellum and the development of a late-onset neurologic syndrome characterized by persistent tremor and gait disturbance (Peters et al., 1991).
Gallagher et al. (2001) used an ANK promoter linked to an A-gamma-globin (HBG1;142200) reporter gene in an erythroid-specific, position-independent, copy number-dependent fashion in transgenic mice to study spherocytosis-associated promoter mutations. They detected abnormalities in reporter gene mRNA and protein expression. Mice with the wildtype promoter demonstrated normal expression in all erythrocytes, whereas mice with the -108T-C promoter mutation (612641.0002) demonstrated varied expression. Undetectable or significantly lower expression was found in mice with linked -108T-C and -153G-A (612641.0006) promoter mutations.Gallagher et al. (2001) concluded that functional defects can be caused by HS-related ankyrin gene promoter mutations.
Salomao et al. (2010) found that glycophorin C (GPC, or GYPC;110750) partitioning was unperturbed in nb/nb cells: GPC sorted to nascent reticulocytes in both wildtype and nb/nb enucleating erythroblasts. In addition, glycophorin A (GPA;617922), band 3 (SLC4A1;109270), and Rh antigen (RH;111700) distributed predominantly to reticulocytes in wildtype enucleating erythroblasts. However, band 3, GPA, and Rh antigen sorted to both expelled nuclei and reticulocytes in nb/nb enucleating erythroblasts. The findings demonstrated that, in mature nb/nb red cells, a mechanism involving abnormal sorting during nuclear extrusion results in multiple protein deficiencies.Salomao et al. (2010) also raised the possibility that reticulocytes in hereditary spherocytosis may differ from normal reticulocytes in their biophysical properties of membrane cohesion or membrane deformability. The results also showed that cytoskeletal attachments are an important factor in regulating transmembrane protein sorting to reticulocytes.
In a kindred with autosomal dominant hereditary spherocytosis (SPH1;182900),Jarolim et al. (1995) identified a unique mutation in the regulatory domain of ankyrin associated with a marked and selective deficiency of ankyrin isoform 2.1 and a normal content of ankyrin isoform 2.2. The deficiency of the 2.1 ankyrin isoform was accompanied by a proportional deficiency of spectrin. The genetic defect was a nonsense mutation glu1669-to-ter (GAA-to-TAA) in 1 allele of the ANK1 gene. Only normal 2.1 mRNA was detected in the reticulocyte RNA. The regulatory domain of ankyrin is subject to extensive alternative splicing. In the case of this mutation, alternative splicing within the regulatory domain of ankyrin retained codon 1669 in ankyrin 2.1 mRNA and removed it from ankyrin 2.2 mRNA.Jarolim et al. (1995) proposed that the glu1669-to-ter mutation decreased the stability of the abnormal ankyrin 2.1 mRNA allele, leading to a decreased synthesis of ankyrin 2.1 and a secondary deficiency of spectrin. The mutant ankyrin was named for the city of origin, Rakovnik, in the Czech Republic.
This variant, formerly titled SPHEROCYTOSIS, TYPE 1, AUTOSOMAL RECESSIVE, has been reclassified as an ANK1 polymorphism based on the allele frequency of the variant in the gnomAD database (v.2.1.1) (Hamosh, 2021).
Eber et al. (1996) found that the ankyrin-1 promoter mutation, -108 T-to-C, is particularly common in recessive hereditary spherocytosis (SPH1;182900). The mutation lies immediately upstream of a first (minor) transcription start site in the promoter region. They stated that because the mutation is silent in heterozygotes, patients with recessive HS must have a second mutation in the other allele. In 1 patient this was a missense mutation, V463I, in the band-3-binding domain of ankyrin-1. Notably, the patient's red cells were more deficient in band 3 than in ankyrin-1 or spectrin (182860), which is opposite to the trend in other ankyrin-1 defects. The second mutation in another patient created an amino acid change in a rare alternate splice product and potentially a cryptic 5-prime splice site.
Hamosh (2021) noted that the c.108T-C variant was present in 1,305 of 31,334 alleles and in 69 homozygotes in the gnomAD database (v.2.1.1), with an allele frequency of 0.04165.
In a kindred with autosomal dominant hereditary spherocytosis (SPH1;182900),Hayette et al. (1998) described a TGG-to-TGA transition in exon 39 of the ANK1 gene resulting in a trp1721-to-ter stop mutation and truncation of the ankyrin protein.
In 2 families with autosomal dominant hereditary spherocytosis (SPH1;182900),Hayette et al. (1998) identified heterozygosity for an ANK1 truncating mutation: codon 1833 in exon 41 was converted from CGA (arg) to TGA (stop).
In 3 unrelated probands from different ethnic backgrounds who had severe hereditary spherocytosis (SPH1;182900) requiring splenectomy,Gallagher et al. (2000) found the same frameshift mutation in exon 4, insertion of an extra cytosine nucleotide at codon 506 of the ANK1 gene. The patients were of Italian, Portuguese, and German extraction and the mutation was on a different haplotype in each.
Leite et al. (2000) identified a heterozygous G-to-A transition at position -153 of the ANK1 promoter in a Brazilian kindred with ankyrin-deficient recessive spherocytosis (SPH1;182900). The -153G-A mutation was always found in cis with the -108C-T mutation (612641.0002), and these linked mutations were silent in the heterozygous state.
In a Turkish boy with severe autosomal recessive spherocytosis (SPH1;182900), born of consanguineous parents,Edelman et al. (2007) identified a homozygous G-to-A transition in intron 16 of the ANK1 gene (IVS16AS-17G-A). The family had previously been reported byDuru et al. (1992). Each parent, who had a milder form of spherocytosis, was heterozygous for the mutation.Edelman et al. (2007) used denaturing high-performance liquid chromatography (DHPLC) to identify the mutation. RT-PCR of patient reticulocytes detected 9 abnormal splice isoforms of ANK1 and no wildtype isoforms, indicating that the mutation interrupted normal transcription.
In a female German patient with moderate spherocytosis (SPH1;182900),Eber et al. (1996) identified a 20-bp deletion in exon 6 of the ANK1 gene, resulting in frameshift and premature termination. Subsequently, following reexamination of the patient,Gallagher et al. (2005) identified compound heterozygosity for the 20-bp deletion and a 2-bp deletion (-72delTG;612641.0009) in the ANK1 promoter adjacent to a transcription initiation site. Both parents had normal hematocrits, increased reticulocyte counts, and abnormal erythrocyte incubated osmotic fragility, typical for the diagnosis of HS with compensated hemolysis. The mother carried the 20-bp deletion. The father was presumed to carry the 2-bp deletion but was deceased, and there was no genetic material available for testing. In vitro analysis of the mutant promoter showed decreased levels of ANK1 expression, altered transcription initiation site utilization and defective binding of TATA-binding protein (TBP;600075) and TFIID (TAF1;313650) complex formation. In a transgenic mouse model, the mutant ankyrin promoter led to abnormalities in ANK1 expression, including decreased expression of a reporter gene and altered transcription initiation site utilization. The authors concluded that the promoter mutation altered ANK1 gene transcription and contributes to the HS phenotype by decreasing ankyrin gene synthesis via disruption of TFIID complex interactions with the ankyrin core promoter.Gallagher et al. (2005) proposed that in promoters that lack conserved cis elements, the TFIID complex may direct preinitiation complex formation at specific sites in core promoter DNA.
For discussion of the 2-bp deletion in the ANK1 gene (-72delTG) that was found in compound heterozygous state in a patient with moderate spherocytosis (SPH1;182900) byGallagher et al. (2005), see612641.0008.
Davies, K. A., Lux, S. E.Hereditary disorders of the red cell membrane skeleton. Trends Genet. 5: 222-227, 1989. [PubMed:2675425,related citations] [Full Text]
Duru, F., Gurgey, A., Ozturk, G., Yorukan, S., Altay, C.Homozygosity for dominant form of hereditary spherocytosis. Brit. J. Haemat. 82: 596-600, 1992. [PubMed:1486040,related citations] [Full Text]
Eber, S. W., Gonzalez, J. M., Lux, M. L., Scarpa, A. L., Tse, W. T., Dornwell, M., Herbers, J., Kugler, W., Ozcan, R., Pekrun, A., Gallagher, P. G., Schroter, W., Forget, B. G., Lux, S. E.Ankyrin-1 mutations are a major cause of dominant and recessive hereditary spherocytosis. Nature Genet. 13: 214-218, 1996. [PubMed:8640229,related citations] [Full Text]
Edelman, E. J., Maksimova, Y., Duru, F., Altay, C., Gallagher, P. G.A complex splicing defect associated with homozygous ankyrin-deficient hereditary spherocytosis. Blood 109: 5491-5493, 2007. [PubMed:17327413,images,related citations] [Full Text]
Gallagher, P. G., Ferreira, J. D. S., Costa, F. F., Saad, S. T. O., Forget, B. G.A recurrent frameshift mutation of the ankyrin gene associated with severe hereditary spherocytosis. Brit. J. Haemat. 111: 1190-1193, 2000. [PubMed:11167760,related citations] [Full Text]
Gallagher, P. G., Forget, B. G.An alternate promoter directs expression of a truncated, muscle-specific isoform of the human ankyrin 1 gene. J. Biol. Chem. 273: 1339-1348, 1998. [PubMed:9430667,related citations] [Full Text]
Gallagher, P. G., Nilson, D. G., Wong, C., Weisbein, J. L., Garrett-Beal, L. J., Eber, S. W., Bodine, D. M.A dinucleotide deletion in the ankyrin promoter alters gene expression, transcription initiation and TFIID complex formation in hereditary spherocytosis. Hum. Molec. Genet. 14: 2501-2509, 2005. [PubMed:16037067,related citations] [Full Text]
Gallagher, P. G., Sabatino, D. E., Basseres, D. S., Nilson, D. M., Wong, C., Cline, A. P., Garrett, L. J., Bodine, D. M.Erythrocyte ankyrin promoter mutations associated with recessive hereditary spherocytosis cause significant abnormalities in ankyrin expression. J. Biol. Chem. 276: 41683-41689, 2001. [PubMed:11527968,related citations] [Full Text]
Hamosh, A.Personal Communication. Baltimore, Md. 6/23/2021.
Hayette, S., Carre, G., Bozon, M., Alloisio, N., Maillet, P., Wilmotte, R., Pascal, O., Reynaud, J., Reman, O., Stephan, J.-L., Morle, L., Delaunay, J.Two distinct truncated variants of ankyrin associated with hereditary spherocytosis. Am. J. Hemat. 58: 36-41, 1998. [PubMed:9590147,related citations] [Full Text]
Jarolim, P., Rubin, H. L., Brabec, V., Palek, J.A nonsense mutation glu1669-to-ter within the regulatory domain of human erythroid ankyrin leads to a selective deficiency of the major ankyrin isoform (band 2.1) and a phenotype of autosomal dominant hereditary spherocytosis. J. Clin. Invest. 95: 941-947, 1995. [PubMed:7883994,related citations] [Full Text]
Lambert, S., Yu, H., Prchal, J. T., Lawler, J., Ruff, P., Speicher, D., Cheung, M. C., Kan, Y. W., Palek, J.cDNA sequence for human erythrocyte ankyrin. Proc. Nat. Acad. Sci. 87: 1730-1734, 1990. [PubMed:1689849,related citations] [Full Text]
Lange, S., Perera, S., Teh, P., Chen, J.Obscurin and KCTD6 regulate cullin-dependent small ankyrin-1 (sAnk1.5) protein turnover. Molec. Biol. Cell 23: 2490-2504, 2012. [PubMed:22573887,images,related citations] [Full Text]
Leite, R. C. A., Basseres, D. S., Ferreira, J. S., Alberto, F. L., Costa, F. F., Saad, S. T. O.Low frequency of ankyrin mutations in hereditary spherocytosis: identification of three novel mutations. Hum. Mutat. 16: 529 only, 2000. [PubMed:11102985,related citations] [Full Text]
Lux, S. E., John, K. M., Bennett, V.Analysis of cDNA for human erythrocyte ankyrin indicates a repeated structure with homology to tissue-differentiation and cell-cycle control proteins. Nature 344: 36-42, 1990. [PubMed:2137557,related citations] [Full Text]
Peters, L. L., Birkenmeier, C. S., Bronson, R. T., White, R. A., Lux, S. E., Otto, E., Bennett, V., Higgins, A., Barker, J. E.Purkinje cell degeneration associated with erythroid ankyrin deficiency in nb/nb mice. J. Cell Biol. 114: 1233-1241, 1991. [PubMed:1716634,related citations] [Full Text]
Salomao, M., Chen, K., Villalobos, J., Mohandas, N., An, X., Chasis, J. A.Hereditary spherocytosis and hereditary elliptocytosis: aberrant protein sorting during erythroblast enucleation. Blood 116: 267-269, 2010. [PubMed:20339087,images,related citations] [Full Text]
Tse, W. T., Meninger, J., Ward, D., John, K., Lux, S. E., Forget, B. G.Genomic cloning and chromosomal sublocalization of the human ankyrin gene. (Abstract) Clin. Res. 38: 266A, 1990.
White, R. A., Birkenmeier, C. S., Lux, S. E., Barker, J. E.Ankyrin and the hemolytic anemia mutation, nb, map to mouse chromosome 8: presence of the nb allele is associated with a truncated erythrocyte ankyrin. Proc. Nat. Acad. Sci. 87: 3117-3121, 1990. [PubMed:2139228,related citations] [Full Text]
White, R., Barker, J.Normoblastosis, a mutant mouse with severe hemolytic anemia. (Abstract) Blood 70S: 57a, 1987.
Alternative titles; symbols
Other entities represented in this entry:
HGNC Approved Gene Symbol: ANK1
Cytogenetic location: 8p11.21 Genomic coordinates(GRCh38) : 8:41,653,225-41,896,741(from NCBI)
| Location | Phenotype | Phenotype MIM number | Inheritance | Phenotype mapping key |
|---|---|---|---|---|
| 8p11.21 | Spherocytosis, type 1 | 182900 | Autosomal dominant; Autosomal recessive | 3 |
By analysis of cDNA for human erythroid ankyrin, Lux et al. (1990) determined that the mature protein contains 1,880 amino acids comprising an N-terminal domain binding integral membrane proteins and tubulin, a central domain binding spectrin and vimentin, and an acidic C-terminal 'regulatory' domain containing an alternatively spliced sequence missing from ankyrin variant 2.2. The N-terminal domain is composed almost entirely of 22 tandem 33-amino acid repeats.
Lambert et al. (1990) found that the cDNA sequence has a large open reading frame of 5,636 basepairs coding for a polypeptide of 1,879 amino acids for the predicted molecular mass of 206 kD. Ankyrin comprises a band-3 (SLC4A1; 109270)-binding domain, a spectrin-binding domain, and a regulatory domain. The band-3-binding domain consists of 23 homologous repeats, each 33 amino acids in length. The regulatory domain differs in length in the 2 isoforms of ankyrin, proteins 2.1 and 2.2.
By Northern blot analysis of human skeletal muscle tissue with an erythroid ANK1 probe, Gallagher and Forget (1998) detected expression of 2.3- and 1.6-kb transcripts, much smaller than the 7.3- and 9.0-kb transcripts observed in erythroid tissue RNA. Using a 5-prime RACE skeletal muscle product as probe, they identified a cDNA encoding a 155-amino acid protein. Secondary structure analysis predicted the presence of a highly charged N-terminal domain followed by a C-terminal domain composed of alternating alpha helix and beta sheet. The membrane-binding domain, the spectrin/fodrin-binding domain, and most of the regulatory domains found in the erythroid form of ANK1 are missing. Genomic sequence analysis determined that the smaller transcript contains 4 exons, a novel exon 1 followed by the erythroid exons 40, 41, and 42, spread over approximately 10 kb. Exon 1 is located in intron 39 of the erythroid ANK gene. Northern blot analysis revealed abundant expression of the 2.3- and 1.6-kb transcripts restricted to skeletal and cardiac muscle with lesser amounts of 3.7- and 7.0-kb transcripts. Immunoblot analysis showed that muscle ANK1 is readily detected as 28- and 30-kD proteins in skeletal muscle but that detection of 70-kD and 210-kD proteins in erythrocyte membranes requires prolonged exposure.
Tse et al. (1990) described the structure of the ANK1 gene corresponding to the domain structure of the protein.
By fluorescence-based in situ hybridization, Tse et al. (1990) localized the ankyrin gene to chromosome 8p11.2. Lux et al. (1990) independently reported localization of ANK1 to chromosome 8p11.2 by FISH analysis.
Using a yeast-2-hybrid screen, Lange et al. (2012) found that the obscurin (OBSCN; 608616)-interacting isoform of human ankyrin-1, sANK1.5, also interacted with human KCTD6 (618791) in striated muscle. Obscurin-binding domain-2 of sANK1.5 interacted with the N-terminal BTB/POZ domain of KCTD6. The interaction was promoted by acetylation of sANK1.5 C-terminal lysines, and subsequent sANK1.5 protein turnover depended on KCTD6-associated neddylation and ubiquitylation, as well as the oligomerization state of the protein. KCTD6 was upregulated during muscle development and mediated association of sANK1.5 with cullin-3 (CUL3; 603136), thereby regulating turnover of sANK1.5. Characterization of KCTD6 binding revealed that KCTD6 formed parallel homotetramers. The N-terminal BTB/POZ domain of KCTD6 was important for initial dimerization, whereas its C terminus was important for complete tetramerization and regulation of its interaction with CUL3 substrate proteins. Regulation of cullin-dependent sANK1.5 turnover depended on the presence of obscurin, as obscurin-knockout mouse muscle displayed reduced sAnk1.5 levels and mislocalization of the sAnk1.5/Kctd6 complex.
Davies and Lux (1989) stated that dosage analysis in 2 hereditary spherocytosis patients with chromosome 8p11 deletions showed them to be hemizygous for the ankyrin gene. A corresponding reduction of approximately 50% in the amount of ankyrin protein was also seen in these patients, who had mental retardation in addition to the red cell defect. In both normoblastosis mice and hereditary spherocytosis humans, spectrin is also reduced as a secondary phenomenon.
Eber et al. (1996) screened all 42 coding exons plus the 5-prime untranslated/promoter region of ankyrin-1 and the 19 coding exons of band 3 (SLC4A1; 109270) in 46 hereditary spherocytosis families. They identified 12 ankyrin-1 mutations and 5 band-3 mutations. Missense mutations and a mutation in the putative ankyrin-1 promoter were stated to be common in recessive HS (see 612641.0002). In contrast, ankyrin-1 and band 3 frameshift and nonsense null mutations prevailed in dominant HS. Increased accumulation of the normal protein product partially compensated for the ankyrin-1 or band 3 defects in some of these null mutations. The findings indicated to Eber et al. (1996) that ankyrin-1 mutations are a major cause of dominant and recessive HS (between 35 and 65%), that band 3 mutations are less common (between 15 and 25%), and that the severity of HS is modified by factors other than the primary gene defect.
In the proband reported by Duru et al. (1992), Edelman et al. (2007) identified a homozygous splice site mutation in the ANK1 gene (612641.0007). Each parent was heterozygous for the mutation.
Mice with normoblastosis (nb/nb) have a deficiency of ankyrin. The nb locus maps to mouse chromosome 8 in a segment that shows homology of synteny with human 8p (White and Barker, 1987). White et al. (1990) used immunologic and biochemical methods to demonstrate an altered (150 kD) immunoreactive ankyrin in homozygous (nb/nb) and heterozygous (nb/+) reticulocytes.
Mice deficient in ankyrin have, in addition to hemolytic anemia, significant neurologic dysfunction associated with Purkinje cell degeneration in the cerebellum and the development of a late-onset neurologic syndrome characterized by persistent tremor and gait disturbance (Peters et al., 1991).
Gallagher et al. (2001) used an ANK promoter linked to an A-gamma-globin (HBG1; 142200) reporter gene in an erythroid-specific, position-independent, copy number-dependent fashion in transgenic mice to study spherocytosis-associated promoter mutations. They detected abnormalities in reporter gene mRNA and protein expression. Mice with the wildtype promoter demonstrated normal expression in all erythrocytes, whereas mice with the -108T-C promoter mutation (612641.0002) demonstrated varied expression. Undetectable or significantly lower expression was found in mice with linked -108T-C and -153G-A (612641.0006) promoter mutations. Gallagher et al. (2001) concluded that functional defects can be caused by HS-related ankyrin gene promoter mutations.
Salomao et al. (2010) found that glycophorin C (GPC, or GYPC; 110750) partitioning was unperturbed in nb/nb cells: GPC sorted to nascent reticulocytes in both wildtype and nb/nb enucleating erythroblasts. In addition, glycophorin A (GPA; 617922), band 3 (SLC4A1; 109270), and Rh antigen (RH; 111700) distributed predominantly to reticulocytes in wildtype enucleating erythroblasts. However, band 3, GPA, and Rh antigen sorted to both expelled nuclei and reticulocytes in nb/nb enucleating erythroblasts. The findings demonstrated that, in mature nb/nb red cells, a mechanism involving abnormal sorting during nuclear extrusion results in multiple protein deficiencies. Salomao et al. (2010) also raised the possibility that reticulocytes in hereditary spherocytosis may differ from normal reticulocytes in their biophysical properties of membrane cohesion or membrane deformability. The results also showed that cytoskeletal attachments are an important factor in regulating transmembrane protein sorting to reticulocytes.
In a kindred with autosomal dominant hereditary spherocytosis (SPH1; 182900), Jarolim et al. (1995) identified a unique mutation in the regulatory domain of ankyrin associated with a marked and selective deficiency of ankyrin isoform 2.1 and a normal content of ankyrin isoform 2.2. The deficiency of the 2.1 ankyrin isoform was accompanied by a proportional deficiency of spectrin. The genetic defect was a nonsense mutation glu1669-to-ter (GAA-to-TAA) in 1 allele of the ANK1 gene. Only normal 2.1 mRNA was detected in the reticulocyte RNA. The regulatory domain of ankyrin is subject to extensive alternative splicing. In the case of this mutation, alternative splicing within the regulatory domain of ankyrin retained codon 1669 in ankyrin 2.1 mRNA and removed it from ankyrin 2.2 mRNA. Jarolim et al. (1995) proposed that the glu1669-to-ter mutation decreased the stability of the abnormal ankyrin 2.1 mRNA allele, leading to a decreased synthesis of ankyrin 2.1 and a secondary deficiency of spectrin. The mutant ankyrin was named for the city of origin, Rakovnik, in the Czech Republic.
This variant, formerly titled SPHEROCYTOSIS, TYPE 1, AUTOSOMAL RECESSIVE, has been reclassified as an ANK1 polymorphism based on the allele frequency of the variant in the gnomAD database (v.2.1.1) (Hamosh, 2021).
Eber et al. (1996) found that the ankyrin-1 promoter mutation, -108 T-to-C, is particularly common in recessive hereditary spherocytosis (SPH1; 182900). The mutation lies immediately upstream of a first (minor) transcription start site in the promoter region. They stated that because the mutation is silent in heterozygotes, patients with recessive HS must have a second mutation in the other allele. In 1 patient this was a missense mutation, V463I, in the band-3-binding domain of ankyrin-1. Notably, the patient's red cells were more deficient in band 3 than in ankyrin-1 or spectrin (182860), which is opposite to the trend in other ankyrin-1 defects. The second mutation in another patient created an amino acid change in a rare alternate splice product and potentially a cryptic 5-prime splice site.
Hamosh (2021) noted that the c.108T-C variant was present in 1,305 of 31,334 alleles and in 69 homozygotes in the gnomAD database (v.2.1.1), with an allele frequency of 0.04165.
In a kindred with autosomal dominant hereditary spherocytosis (SPH1; 182900), Hayette et al. (1998) described a TGG-to-TGA transition in exon 39 of the ANK1 gene resulting in a trp1721-to-ter stop mutation and truncation of the ankyrin protein.
In 2 families with autosomal dominant hereditary spherocytosis (SPH1; 182900), Hayette et al. (1998) identified heterozygosity for an ANK1 truncating mutation: codon 1833 in exon 41 was converted from CGA (arg) to TGA (stop).
In 3 unrelated probands from different ethnic backgrounds who had severe hereditary spherocytosis (SPH1; 182900) requiring splenectomy, Gallagher et al. (2000) found the same frameshift mutation in exon 4, insertion of an extra cytosine nucleotide at codon 506 of the ANK1 gene. The patients were of Italian, Portuguese, and German extraction and the mutation was on a different haplotype in each.
Leite et al. (2000) identified a heterozygous G-to-A transition at position -153 of the ANK1 promoter in a Brazilian kindred with ankyrin-deficient recessive spherocytosis (SPH1; 182900). The -153G-A mutation was always found in cis with the -108C-T mutation (612641.0002), and these linked mutations were silent in the heterozygous state.
In a Turkish boy with severe autosomal recessive spherocytosis (SPH1; 182900), born of consanguineous parents, Edelman et al. (2007) identified a homozygous G-to-A transition in intron 16 of the ANK1 gene (IVS16AS-17G-A). The family had previously been reported by Duru et al. (1992). Each parent, who had a milder form of spherocytosis, was heterozygous for the mutation. Edelman et al. (2007) used denaturing high-performance liquid chromatography (DHPLC) to identify the mutation. RT-PCR of patient reticulocytes detected 9 abnormal splice isoforms of ANK1 and no wildtype isoforms, indicating that the mutation interrupted normal transcription.
In a female German patient with moderate spherocytosis (SPH1; 182900), Eber et al. (1996) identified a 20-bp deletion in exon 6 of the ANK1 gene, resulting in frameshift and premature termination. Subsequently, following reexamination of the patient, Gallagher et al. (2005) identified compound heterozygosity for the 20-bp deletion and a 2-bp deletion (-72delTG; 612641.0009) in the ANK1 promoter adjacent to a transcription initiation site. Both parents had normal hematocrits, increased reticulocyte counts, and abnormal erythrocyte incubated osmotic fragility, typical for the diagnosis of HS with compensated hemolysis. The mother carried the 20-bp deletion. The father was presumed to carry the 2-bp deletion but was deceased, and there was no genetic material available for testing. In vitro analysis of the mutant promoter showed decreased levels of ANK1 expression, altered transcription initiation site utilization and defective binding of TATA-binding protein (TBP; 600075) and TFIID (TAF1; 313650) complex formation. In a transgenic mouse model, the mutant ankyrin promoter led to abnormalities in ANK1 expression, including decreased expression of a reporter gene and altered transcription initiation site utilization. The authors concluded that the promoter mutation altered ANK1 gene transcription and contributes to the HS phenotype by decreasing ankyrin gene synthesis via disruption of TFIID complex interactions with the ankyrin core promoter. Gallagher et al. (2005) proposed that in promoters that lack conserved cis elements, the TFIID complex may direct preinitiation complex formation at specific sites in core promoter DNA.
For discussion of the 2-bp deletion in the ANK1 gene (-72delTG) that was found in compound heterozygous state in a patient with moderate spherocytosis (SPH1; 182900) by Gallagher et al. (2005), see 612641.0008.
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