Alternative titles; symbols
ORPHA: 822; DO: 0110916;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 8p11.21 | Spherocytosis, type 1 | 182900 | Autosomal dominant; Autosomal recessive | 3 | ANK1 | 612641 |
A number sign (#) is used with this entry because of evidence that spherocytosis type 1 (SPH1) is caused by heterozygous, compound heterozygous, or homozygous mutation in the gene encoding ankyrin (ANK1; 612641) on chromosome 8p11.
Hereditary spherocytosis refers to a group of heterogeneous disorders that are characterized by the presence of spherical-shaped erythrocytes (spherocytes) on the peripheral blood smear. The disorders are characterized clinically by anemia, jaundice, and splenomegaly, with variable severity. Common complications include cholelithiasis, hemolytic episodes, and aplastic crises (review by Perrotta et al., 2008).
Elgsaeter et al. (1986) gave an extensive review of the molecular basis of erythrocyte shape with a discussion of the role of spectrin and other proteins such as ankyrin, actin (102630), band 4.1 (130500), and band 3 (109270), all of which is relevant to the understanding of spherocytosis and elliptocytosis (see 611904).
See Delaunay (2007) for a discussion of the molecular basis of hereditary red cell membrane disorders.
Genetic Heterogeneity of Hereditary Spherocytosis
Also see SPH2 (616649), caused by mutation in the SPTB gene (182870) on chromosome 14q23; SPH3 (270970), caused by mutation in the SPTA1 gene (182860) on chromosome 1q21; SPH4 (612653), caused by mutation in the SLC4A1 gene (109270) on chromosome 17q21; and SPH5 (612690), caused by mutation in the EPB42 gene (177070) on chromosome 15q15.
MacKinney et al. (1962) and Morton et al. (1962) studied 26 families with spherocytosis. They concluded that after the initial case in a family has been identified, 4 tests suffice for the diagnosis in other family members: smear, reticulocyte count, hemoglobin, and bilirubin. The fragility test (increased osmotic fragility characterizes the disease) is unnecessary after the diagnosis has been made in the proband. It was estimated that the prevalence is 2.2 per 10,000, that the mutation rate is 0.000022 and that about one-fourth of cases are sporadic. No evidence of reproductive compensation or of increased prenatal and infant mortality was found. No enzyme defect was identified (Miwa et al., 1962).
Several observations suggest that more than one type of hereditary spherocytosis exists in man (review by Zail et al., 1967).
Barry et al. (1968) pointed out that hemochromatosis is a serious complication of untreated spherocytosis. Fargion et al. (1986) described 2 brothers who were thought to be heterozygous for the hemochromatosis gene and who also were affected with hereditary spherocytosis. Both had severe iron overload whereas all relatives without hereditary spherocytosis, including those with HLA haplotypes identical to those of the 2 brothers, had normal iron stores. Montes-Cano et al. (2003) reported a similar situation in a Spanish family: 3 members of different generations were diagnosed with hereditary spherocytosis and 1 of them, 44 years of age, presented with iron overload with hepatic deposit and required treatment with periodic phlebotomies. Other members of the family showed normal values in iron metabolism. The patient with iron overload was a compound heterozygote for the H63D (613609.0002) and C282Y (613609.0001) mutations in the HFE gene.
In a family with 6 persons affected in 3 generations, Wiley and Firkin (1970) found a form of hereditary spherocytosis with unusual features; other reports of atypical disease were reviewed.
Aksoy et al. (1974) described severe hemolytic anemia in a patient seemingly with both elliptocytosis (inherited probably from the father) and spherocytosis (inherited from the mother). This finding raises a question of possible allelism of spherocytosis and one form of elliptocytosis. A genetic compound is more likely to show summation of effects than is a double heterozygote.
Epidemic aplastic crisis in congenital chronic hemolytic anemias has been attributed to the human parvovirus (HPV) which also causes erythema infectiosum, or fifth disease (Tsukada et al., 1985; Rao et al., 1983). Lefrere et al. (1986) showed that in both children and adults the human parvovirus can precipitate aplastic crisis in hereditary spherocytosis just as it does in other forms of hereditary hemolytic anemia, particularly sickle cell disease. Healthy persons probably develop an erythroblastopenia when experiencing their first contact with HPV, but this escapes notice when the normal red cell life span allows maintenance of hemoglobin level throughout the interruption of red cell production. Ng et al. (1987) described a father and a son in whom aplastic crisis in hereditary spherocytosis was precipitated by parvovirus infection.
Moiseyev et al. (1987) described a kindred in which hereditary spherocytosis occurred in combination with hypertrophic cardiomyopathy in 5 individuals in 4 successive generations. In another branch of the family, 4 individuals in 3 successive generations had either hereditary spherocytosis or hypertrophic cardiomyopathy (192600), but not both.
Coetzer et al. (1988) described a 41-year-old man and an unrelated 49-year-old woman who had atypical, severe spherocytosis with partial response to splenectomy. No information on the family aided in evaluating inheritance in the second case; in the first case, the deceased father had had chronic anemia and a sib had died at age 3 months of unknown cause. In these 2 patients, the authors found a partial deficiency of ankyrin and spectrin in red cells. Coetzer et al. (1988) concluded that a defect in synthesis of ankyrin was the primary abnormality.
In the offspring of first-cousin parents, both of whom had hereditary spherocytosis, Duru et al. (1992) observed a 6-month-old male infant with severe anemia. The infant required red blood cell transfusions starting at the age of 1 month and continuing until splenectomy was performed at the age of 1 year to produce a complete hematologic remission. Duru et al. (1992) concluded that this represented an example of homozygosity for the spherocytosis gene, presumably an ankyrin mutant, and that splenectomy can cure the anemia, even in the homozygote.
Both sickle cell anemia and hereditary spherocytosis are known causes of leg ulcers. Peretz et al. (1997) reported the case of an 18-year-old Bedouin with leg ulcers of 12-months duration; past history revealed HS since childhood. Treatment for 6 months with various conservative modalities had no effect on the ulcers. However, complete clearance was achieved 2 months after splenectomy.
The precocious formation of bilirubinate gallstones is the most common complication of hereditary spherocytosis, and the prevention of this problem represents a major impetus for splenectomy in many patients with compensated hemolysis. Because Gilbert syndrome (143500) had been considered a risk factor for gallstone formation, del Giudice et al. (1999) postulated that the association of this common inherited disorder of hepatic bilirubin metabolism with hereditary spherocytosis could increase cholelithiasis. To test this hypothesis, 103 children with mild to moderate hereditary spherocytosis who, from age 1 year, had undergone a liver and biliary tree ultrasonography every year, were retrospectively examined. The 2-bp TA insertion within the promoter of the UGT1A1 gene (191740.0011), which is associated with Gilbert syndrome, was screened. The risk of developing gallstones was statistically different among the 3 groups of patients (homozygotes for the normal UGT1A1 allele, heterozygotes, and homozygotes for the allele with the TA insertion). del Giudice et al. (1999) concluded that although patients with hereditary spherocytosis were the only ones studied, extrapolating these findings to patients who have different forms of inherited (e.g., thalassemia, intraerythrocytic enzymatic deficiency) or acquired (e.g., autoimmune hemolytic anemia, hemolysis from mechanical heart valve replacement) chronic hemolysis may be warranted.
Reviews
Davies and Lux (1989) gave a useful review of hereditary disorders of the red cell membrane skeleton. They referred to a form of spherocytosis due to a defect in ankyrin as spherocytosis-1 and a form due to a defect in beta-spectrin as spherocytosis-2.
Perrotta et al. (2008) reviewed the several forms of hereditary spherocytosis.
On behalf of the General Haematology Task Force of the British Committee for Standards in Haematology, Bolton-Maggs et al. (2004) provided comprehensive guidelines for the diagnosis and management of hereditary spherocytosis.
Kimberling et al. (1975) demonstrated linkage between spherocytosis and a translocation involving the short arms of chromosomes 8 and 12. They concluded that the spherocytosis locus is either very close to the centromere of chromosome 8 or on 12p. Kimberling et al. (1978) reported further on their studies of a family with HS and an 8-12 translocation. They concluded that a locus for HS is located near the breakpoint of the translocation.
Cohen et al. (1991) described 2 sibs in whom congenital spherocytosis was associated with an inherited interstitial deletion of 8p, del8(p11-p21). This abnormal chromosome was inherited from their mother who showed this deletion as well as a small fragment representing the deleted segment. Centromeric material from chromosome 8 was detected in this chromosome fragment by in situ hybridization using an alpha-satellite probe, but not by C banding. Chromosome analysis of skin fibroblasts from the mother and a third sib, both normal but with a similar karyotype, showed the deleted fragment in over 80% of cells. Since the chromosome abnormality was not observed in 5 of the mother's sibs, it probably arose de novo in her. The 2 sibs with congenital spherocytosis had multiple other phenotypic abnormalities. The male had short stature, severe mental retardation, microcephaly, and micrognathia with bat ears, primary failure of sexual development, and bilateral conductive deafness secondary to congenital stapedial fixation. In addition to these features, the sister had torticollis associated with fusion of several vertebrae; she developed diabetes mellitus at the age of 15 years, which was controlled by diet and chlorpropamide.
Stratton et al. (1992) described an infant with a de novo interstitial deletion of the proximal short arm of chromosome 8 (p21p11.2). The infant had bilateral cleft lip and palate and apparent hypogonadism. Four previous reports of similar deletions (p21p11.1) were associated with hypogonadotropic hypogonadism and hereditary spherocytosis. Since their patient demonstrated no red blood cell abnormality, Stratton et al. (1992) suggested that the gene for HS is located in the region 8p11.2-p11.1.
Bass et al. (1983) presented evidence for the chromosome 8 localization of a spherocytosis locus: they observed mother and son with hereditary spherocytosis and a balanced translocation between chromosomes 3 and 8. The breakpoint on 8 in the family of Kimberling et al. (1975) and in their family was at 8p11.
Chilcote et al. (1987) studied 2 dysmorphic sibs with neurologic findings and hemolytic anemia. Clinical and laboratory findings were consistent with the diagnosis of congenital spherocytosis whereas both parents and 2 unaffected sibs were normal. The 2 affected children had an interstitial deletion of the short arm of chromosome 8, 46,XX,del(8)(p11.1p21.1). Chilcote et al. (1987) suggested that together with the evidence from the families of Kimberling et al. (1975) and Bass et al. (1983), their family provides strong evidence for a gene for congenital spherocytosis in the proximal part of 8p. Glutathione reductase (GSR; 138300) levels were slightly reduced in the 2 affected children relative to their parents and an unaffected sib but did not approach the half-normal values that might be expected and it was unlikely that the moderate reduction in the glutathione reductase activity would cause hemolysis. The presence of abnormalities in 2 sibs with normal parents may have its explanation in mosaicism of 1 parent. Close linkage to GSR, which is located at 8p21, was excluded in the family with hereditary spherocytosis and GSR deficiency reported by Nakashima et al. (1978) in which the traits segregated independently. The deficiency state without hereditary spherocytosis was asymptomatic.
Kitatani et al. (1988) studied a 1-year-old boy with spherocytosis associated with a de novo minute deletion involving 8p21.1-p11.22. Contradictory information on the mapping of hereditary spherocytosis may reflect genetic heterogeneity in this condition as in elliptocytosis.
Costa et al. (1990) identified reports of 5 cases of deletion or translocation involving chromosome 8p and leading to spherocytosis.
Lux et al. (1990) reported that 1 copy of the ankyrin gene was missing from DNA of 2 unrelated children with severe spherocytosis and heterozygous deletion of chromosome 8--del(8)(p11-p21.1). Affected red cells were also ankyrin-deficient.
Okamoto et al. (1995) described a 30-month-old Japanese boy with spherocytic anemia in association with multiple anomalies and mental retardation. The karyotype had a deletion of interstitial deletion of 8p: del(8)(p11.23p21.1). Glutathione reductase activity was moderately reduced, consistent with deletion of that locus as well as of the ankyrin locus. Okamoto et al. (1995) reviewed the other cases of 8p deletion associated with spherocytic anemia.
Jacob and Jandl (1964) were of the view that the primary defect is in the red cell membrane, which is abnormally permeable to sodium.
Jacob et al. (1971) demonstrated altered membrane protein in hereditary spherocytosis. Microfilamentous proteins resembling actin are important to the shape of the red cell. Comparable membrane proteins occur throughout phylogeny under circumstances suggesting a role in cell plasticity and shape. Actin and myosin-like filamentous proteins occur in platelets.
Heterogeneity in hereditary spherocytosis was indicated by studies of structural proteins of the red cell membrane, including alpha and beta spectrin,. actin (see 102630), and protein 4.1 (EPB41; 130500). In a systematic assay of the interactions of spectrin in 6 kindreds with autosomal dominant hereditary spherocytosis, Wolfe et al. (1982) found 1 in which all 4 affected members had reduced enhancement of spectrin-actin binding by protein 4.1, owing to a 39% decrease in the binding of normal protein 4.1 by spectrin. The defective spectrin was separated into 2 populations by affinity chromatography on immobilized normal protein 4.1. One population lacked ability to bind 4.1, but the other functioned normally.
Hill et al. (1982) concluded that 'the difference between HS and normal membranes, which persists in isolated cytoskeletons, suggests that alterations in either the primary structure or the degree of phosphorylation of protein bands 2.1 or 4.1 may be central to the molecular basis of hereditary spherocytosis.' The 2.1 band is also known as ankyrin. The major proteins of the cytoskeleton, spectrin and actin, are attached to the cell membrane by bands 2.1 and 4.1. Johnsson and Himberg (1982) presented evidence that platelets, as well as red cells, are defective in HS.
In a 41-year old man with severe spherocytosis, Coetzer et al. (1988) studied the synthesis, assembly, and turnover of spectrin and ankyrin in the reticulocytes of the first patient. The synthesis of spectrin, when measured in the cell cytosol, was normal (alpha-spectrin; 182860) or increased (beta-spectrin; 182870). The principal defect appeared to be a diminished incorporation of ankyrin into the cell membrane, leading to decreased deposition of spectrin as a secondary phenomenon. Ankyrin is the principal binding site for spectrin on the membrane. Normal red cells contain 1 copy of ankyrin per spectrin tetramer. The red cell membrane skeleton is a submembranous network composed mainly of spectrin, actin, and proteins that migrate on gel electrophoresis as bands 4.1 (EPB41; 130500) and 4.9 (EPB49; 125305). Visualization of the skeleton by electron microscopy shows a primarily hexagonal lattice of fibers of spectrin tetramers linked to junctional complexes containing actin and proteins 4.1 and 4.9. The skeleton is attached to the cell membrane by ankyrin (protein 2.1), which connects beta-spectrin to the cytoplasmic portion of band 3 (SLC4A1; 109270), which is the major integral membrane protein. In addition, protein 4.1 links the distal ends of spectrin tetramers to transmembrane glycoprotein.
Hanspal et al. (1991) concluded that the primary defect underlying the combined spectrin and ankyrin deficiency in severe hereditary spherocytosis is a deficiency of ankyrin mRNA leading to a reduced synthesis of ankyrin, which, in turn, underlies a decreased assembly of spectrin on the membrane.
Using RFLPs defined by a cDNA for human erythrocyte ankyrin, Forget et al. (1989) demonstrated close linkage between hereditary spherocytosis and the ankyrin gene, with no crossovers observed. The calculated lod score was 3.63 at a theta of 0.0. The ankyrin gene appears to be located on the short arm of chromosome 8. The large kindred in which the linkage was established had classic features.
Costa et al. (1990) analyzed a large kindred with typical dominant hereditary spherocytosis for genetic linkage with the genes for alpha spectrin, beta spectrin, protein 4.1, and ankyrin by means of RFLPs. Close linkage was excluded for all of the candidate genes except that for ankyrin, which was found to show no recombination, with a lod score of 3.63.
By fluorescence-based in situ hybridization, Tse et al. (1990) localized the ankyrin gene to 8p11.2.
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.
Iolascon et al. (1991) described 2 Italian families with ankyrin deficiency spherocytosis. In both, the disorder was a new mutation in the proband; 1 proband transmitted it to an offspring.
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 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.
Gallagher and Forget (1998) tabulated a total of 34 mutations in the ANK1 gene that have been associated with hereditary spherocytosis, as contrasted with 2 mutations in the alpha-spectrin gene and 19 in the beta-spectrin gene.
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.
Sengar et al. (1977) presented some fragmentary evidence that HLA and hereditary spherocytosis may be linked.
De Jongh et al. (1982) could demonstrate no linkage of spherocytosis with Gm or with HLA. Lod scores with PI were also negative.
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