HGNC Approved Gene Symbol: SPTA1
SNOMEDCT: 9434008;
Cytogenetic location: 1q23.1 Genomic coordinates (GRCh38) : 1:158,610,704-158,686,715 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1q23.1 | Elliptocytosis-2 | 130600 | Autosomal dominant | 3 |
| Pyropoikilocytosis | 266140 | Autosomal recessive | 3 | |
| Spherocytosis, type 3 | 270970 | Autosomal recessive | 3 |
Spectrin, the predominant component of the membrane skeleton of the red cell, is essential in determining the properties of the membrane including its shape and deformability. It consists of 2 nonidentical subunits, alpha (MW 240,000) and beta (MW 225,000; 182870) (Knowles et al., 1984). Spectrin is present in the red cell membrane in a tetrameric or oligomeric form through head-to-head self-association of heterodimers that are linked by actin (see 102560) polymers and protein 4.1 (130500) to form a 2-dimensional network. Ankyrin (612641) binds the skeleton to the membrane lipid bilayer through its high-affinity association with spectrin beta chains and the integral protein band 3 (109270) of the lipid bilayer.
Sahr et al. (1990) isolated overlapping cDNA clones for the entire coding sequence of human erythroid alpha spectrin. The deduced polypeptide contains 2,429 amino acids and, as noted by Speicher and Marchesi (1984), is composed largely of homologous 106-amino acid repeat units. The protein can be divided into 22 segments, 17 of which are homologous. Only the very N-terminal 22 residues and the C-terminal 150 residues appear to be unrelated to the conserved repeat units.
Kotula et al. (1991) noted that the SPTA gene spans 80 kb and includes 52 exons ranging in size from 18 to 684 bp. They mapped the exons and the intron-exon junctions. The authors speculated that the absence of correlation between exons and the 106-amino acid repeats characteristic of the protein reflects the evolution of a spectrin-like gene from a minigene early in the evolution of eukaryotes.
Birkenmeier et al. (1988) showed that the erythroid alpha-spectrin gene is tightly linked to the spherocytosis locus on mouse chromosome 1, suggesting that a defect in this gene is responsible for spherocytosis in the mouse. Raeymaekers et al. (1988) found that alpha-spectrin is linked to Duffy blood group (FY; 110700) on chromosome 1; the lod score was 3.81 at theta = 0.0. By somatic cell hybrid studies, Huebner et al. (1985) assigned the alpha-spectrin gene to chromosome 1 in both mouse and man. By in situ hybridization, the human gene was localized to 1q22-q25. Since a non-Rh-linked form of elliptocytosis had been very tentatively mapped (maximum lod score = 2.08) to this same region by linkage to Duffy blood group (Keats, 1979; Rao et al., 1979), the defect in that hematologic disorder may involve alpha spectrin. (As this turned out to be the case, this is one of the first examples of positive results from the 'candidate gene' approach to elucidating etiopathogenesis.) In combination with in situ hybridization data, the findings of Middleton-Price et al. (1988) suggested that SPTA may lie within band 1q21. The gene was found to lie proximal to the breakpoint at 1q23 in a balanced X;1 translocation. Another cell line showed 2 alpha-spectrin alleles, consistent with the location of alpha-spectrin in the distal part of 1q21. Pakstis et al. (1989) presented linkage data and analyzed the relationship between the SPTA1 locus and the anonymous DNA fragment D1S75. Pairwise analyses estimated the maximum likelihood of 12.8% recombination for the SPTA1/D1S75 interval with a peak lod score of 5.04. In a linkage map of chromosome 1 prepared by Rouleau et al. (1990), it was concluded that SPTA1 lies 17 cM proximal to Fy.
Kotula et al. (1991) noted that peptide mapping of spectrin partial tryptic digests allowed division of the alpha- and beta-chains into 5 and 4 domains, respectively. The alpha-I and beta-I domains, which face each other, participate in dimer self-association. Elliptocytosis can result from changes in either the alpha-I or beta-I domain; changes in either can result in weakened spectrin dimer self-association.
Knowles et al. (1984) identified polymorphisms in the alpha-II domain of spectrin in Caucasian and black individuals. The polymorphisms did not produce anemia and did not appear to alter the expression of an underlying spherocytosis or elliptocytosis. In family studies, the alpha II 46,000 MW variations were consistent with mendelian inheritance.
Elliptocytosis 2
In blacks, variants of the spectrin alpha subunit have been found: alpha-I/74, alpha-I/46, and alpha-I/65 (Lawler et al., 1984; Lecomte et al., 1985; Lawler et al., 1985). Alloisio et al. (1986) found the alpha-I/65 variant in non-black persons in North Africa where a protein 4.1 defect had been found most often.
Marchesi et al. (1987) reviewed varieties of abnormal spectrins (182860.0001-182860.0004) that have been found in hereditary elliptocytosis (EL2; 130600). All show impaired self-association to form oligomers.
Iarocci et al. (1988) described a 4-year-old Yoruba boy in Nigeria who at birth had severe poikilocytosis, hemolytic anemia, and hyperbilirubinemia requiring exchange transfusion and phototherapy. The poikilocytic anemia was found to be due to compound heterozygosity for 2 alpha-spectrin mutations. The authors indicated that 7 structural mutations of alpha spectrin (designated I/74, I/65, I/61, I/50a, I/50b, and I/43,42) as well as truncated alpha spectrin have been identified in patients with hereditary elliptocytosis or hereditary pyropoikilocytosis by SDS-PAGE evaluation of red cell membrane proteins or by analysis of tryptic peptides following limited digestion.
One class of elliptocytogenic change is spectrin alpha(I/74) which is characterized by an increase in the alpha-I 74-kD fragment at the expense of the parent alpha-I 80-kD fragment. Spectrin Culoz (182860.0006) and spectrin Lyon (182860.0007) are examples of alpha I/74 mutations of the alpha-spectrin chain.
Sahr et al. (1989) used PCR to amplify the appropriate exons in DNA from individuals with 3 variants of hereditary elliptocytosis. In 1, abnormality resulted from a duplication of leucine codon 148 in exon 4; TTG-CTG to TTG-TTG-CTG (182860.0003). In 2 other unrelated cases, 2 separate single base changes were observed in exon 6: CTG to CCG (leucine-to-proline) encoding residue 254, and TCC to CCC (serine-to-proline) encoding residue 255. Furthermore, in 2 unrelated individuals, a single base change of CAG to CCG (glutamine-to-proline) encoding residue 465 in exon 11 was observed.
Pyropoikilocytosis
Lecomte et al. (1985) described abnormality of alpha spectrin in 2 black families with elliptocytosis and pyropoikilocytosis (HPP; 266140). Marchesi et al. (1986) also demonstrated abnormality of alpha spectrin in 2 kindreds with hereditary elliptocytosis. The clinical expression ranged from mild elliptocytosis without hemolysis to severe poikilocytic hemolytic anemia clinically resembling hereditary pyropoikilocytosis.
Lawler et al. (1988) described a severe form of pyropoikilocytosis in a 6-year-old black girl who was a compound heterozygote for 2 distinct alpha-spectrin mutations, a previously detected mutation in tryptic fragment 74 and a new mutation in tryptic fragment 61.
Lecomte et al. (1990) found a new alpha-spectrin variant in a child with severe neonatal hemolytic anemia (182860.0021). The abnormality was thought to be homozygous in the propositus who showed poikilocytosis. No abnormality was detected in the parents, who came from the West Indies and were thought to be unrelated.
Spherocytosis Type 3
Wichterle et al. (1996) described compound heterozygosity for 2 splicing mutations (182860.0022; 182860.0023) in the SPTA1 gene that caused hereditary spherocytosis (SPH3; 270970).
Gallagher and Forget (1996) cataloged 25 alpha-spectrin mutations reported in cases of hereditary elliptocytosis and hereditary pyropoikilocytosis. Three were splicing mutations, 1 was a 3-bp insertion, and the remainder were missense mutations. Gallagher and Forget (1998) tabulated 2 SPTA1 mutations that cause hereditary spherocytosis as contrasted with 19 mutations of the beta-spectrin gene (SPTB; 182870) that are known to cause hereditary spherocytosis. Gallagher and Forget (1998) tabulated 2 mutations of the SPTA gene that caused hereditary spherocytosis.
It has repeatedly been observed that the amount of mutant alpha chain is variable in different individuals with hereditary elliptocytosis, resulting in clinical pictures of variable severity. In a large Algerian family with Sp-alpha(I/65) hereditary elliptocytosis, Guetarni et al. (1990) demonstrated that the different levels are the result of different percentages of the alpha-spectrin allele in trans. In an informative sibship, they found 3 persons with a distinctly high level of expression of the variant, suggesting the existence in trans of a low-percentage alpha-allele (called LE allele for 'low expression'). In contrast, a basal level of expression of the variant in the same sibship indicated the existence in trans of a normal-percentage alpha-allele. Haplotype analysis was also used in the study. This appears to be a superb example of an isoallele affecting the expression of the phenotype resulting from the other allele.
Autosomal dominant elliptocytosis within the same family may be associated with transfusion-dependent hemolytic anemia in some heterozygotes and vigorous good health in others. Motulsky et al. (1954) conjectured that a second genetic defect, normally silent, might be the explanation for this apparent exception to the principles of mendelian genetics. Parquet et al. (1994) and Randon et al. (1994) showed that, in fact, this was the case. The explanation lies in the effects on the assembly of the alpha-spectrin and beta-spectrin chains when a polymorphism exists at another point in the alpha-spectrin molecule which also contains a mutation causing elliptocytosis. The beta chain is synthesized at an early stage of assembly of the erythrocyte cytoskeleton and binds to its attachment site (ankyrin) on the cell membrane. Thereafter, the alpha chain floods the system and the part not taken up into an equimolar complex by the beta chain is destroyed by proteases in the cytosol (Moon and Lazarides, 1983). As demonstrated by Speicher et al. (1992), the mechanism of the lateral association of the constituent chains of the alpha-beta spectrin dimer involves strong interactions between pairs of repeats at one end of the dimer. Randon et al. (1994) found that it is one of these critical repeats that is disturbed by the alpha-LELY mutation. Delaunay and Dhermy (1993), in Lyon, France, had shown that there is a common, but low-expression and symptomless spectrin polymorphism resulting from a substitution toward the far end of the alpha chain; the mutation is designated as alpha-LELY for 'low-expression allele, Lyon.' When freshly synthesized alpha chains are assimilated by the beta chains already on the membrane, the normal alpha chain is preferred to the mutant. With such a high frequency of the alpha-LELY allele in the population, a third of heterozygotes carrying an elliptocytosis mutation at the end of the spectrin alpha chain will also possess an alpha-LELY allele. If both mutations occur in the same alpha chain (that is to say in cis), which will be largely rejected by the membrane-bound beta chain, it will be the normal alpha chain that will be predominantly incorporated into the cytoskeletal network. In this case, the polymorphism acts to rescue the double heterozygote from the worst consequences of the hereditary elliptocytosis. But if the mutations occur in different alpha-chain alleles, then the normal beta-chain binding site will carry the defective dimer binding sites onto the membrane, and the proportion of functional spectrin tetramers will be greatly suppressed; the malign effects of the elliptocytic mutation will be amplified. In some milder forms of hereditary elliptocytosis, the mutation probably only weakens rather than annihilates the association of spectrin dimers. Even in this case (see Perrotta et al., 1994), an offspring with an elliptocytic alpha-chain mutation together with alpha-LELY in trans is more noticeably affected than the father with no alpha-LELY allele. (The situation in which a polymorphism in the gene influences the expression of the primary disease-producing mutation is observed also in the case of the PRNP gene (176640): the asp178-to-asn mutation causes Creutzfeldt-Jakob disease when in cis with val129 (176640.0005), whereas it produces familial fatal insomnia when it is in cis with met129 (176640.0010).)
Randon et al. (1994) referred to the allele in cis as alpha-HE-LELY and the diplotype in trans as alpha-HE/alpha-LELY.
Gallagher and Forget (1993) reviewed all aspects of the alpha and beta spectrin genes in health and disease. Delaunay and Dhermy (1993) reviewed mutations involving the spectrin heterodimer contact site which is critical to normal self-association of spectrin. Self-association allows the dimer to form tetramers or higher order oligomers, and permits the whole skeleton to acquire its mechanical properties. They referred to pyropoikilocytosis as an 'aggravated' form of elliptocytosis. Both are defined on morphologic grounds. Hereditary elliptocytosis shows a wide spectrum of clinical presentations, ranging from the absence of symptoms to severe yet not life-threatening pictures. Pyropoikilocytosis has a narrower spectrum of clinical aspects, ranging from severe to life-threatening syndromes. They pointed to the high incidence of so-called LE (for 'low expression') alleles of the SPTA gene. The compound heterozygous state for an LE allele and an HE allele (hereditary elliptocytosis) results in increased relative expression of the latter, ending in a more severe clinical picture. Remarkably, 4 different mutations have been found in codon 28 of SPTA1: R28L (182860.0011), R28S (182860.0012), R28C (182860.0013), and R28H (182860.0014). All 4 can result in severe pyropoikilocytosis if an LE allele is present in trans. The fact that 4 mutations have been demonstrated in codon 28 and that each of them has been found several times suggests that the CpG dinucleotide is a hotspot for mutation. Delaunay and Dhermy (1993) commented on the high frequency of the leu148-dup mutation (182860.0003), also referred to as the alpha(I/65) mutation, as well as the leu207-to-pro (182860.0016) and leu260-to-pro (182860.0001) mutations. None of these reach as high a frequency as the band 3 mutation accounting for Southeast Asian ovalocytosis (109270.0002) but are sufficiently frequent to raise the question of selective advantage in relation to malaria. In vitro evidence supports this possibility.
By database and phylogenetic analysis, Salomao et al. (2006) showed that the SPTA1 gene is unique to mammals and that it arose through duplication of the SPTAN1 gene (182810). They found that an SPTA1 fragment containing the site of head-to-head interaction with the beta-chain bound more weakly than the corresponding SPTAN1 fragment, and they identified sequences that determined the strength of the dimer-dimer interaction on the membrane. Salomao et al. (2006) concluded that SPTA1 is adapted for rapidly making and breaking tetramers, thus contributing to the deformability of erythrocyte membranes.
This mutation was designated LEU254PRO by Marchesi et al. (1987) and Sahr et al. (1989). For a time the numbering system used for SPTA1 was based on a sequence that lacked the first 6 residues.
This substitution, which resulted from a CTG-to-CCG change in exon 6, was found in patients with elliptocytosis (EL2; 130600) by Marchesi et al. (1987) and Sahr et al. (1989). The mutation results in a Sp-alpha I/46 variant, referring to the molecular weight of the abnormal peptide observed after limited tryptic digestion. This variant appeared to be restricted to the areas of the Gulf of Guinea in west Africa and to be found in closed ethnic groups.
This mutation was designated GLN465PRO by Marchesi et al. (1987) and Sahr et al. (1989). For a time the numbering system used for SPTA1 was based on a sequence that lacked the first 6 residues.
This substitution, which resulted from a CAG-to-CCG change in exon 11, was found in patients with elliptocytosis (EL2; 130600) by Marchesi et al. (1987) and Sahr et al. (1989). The mutation is a Sp-alpha I/50-46b variant.
Marchesi et al. (1987) and Sahr et al. (1989) stated that the duplication occurred after leu148, but it was later found to occur after leu154. For a time the numbering system used for SPTA1 was based on a sequence that lacked the first 6 residues.
This mutation has also been referred to as the alpha(I-65) mutation. In 2 American black patients with elliptocytosis (EL2; 130600), Marchesi et al. (1987) and Sahr et al. (1989) found insertion of an extra leucine residue after leucine-148. Roux et al. (1989) identified the molecular defect in 5 unrelated families in North Africa (Algeria) with the alpha-spectrin form of hereditary elliptocytosis. This form of elliptocytosis is associated with an abnormal 65-kD alpha-I peptide (rather than the normal 80-kD) following limited trypsin digestion of whole spectrin. The authors identified an extra leucine codon (TTG) between codons 147 and 149 in exon 4, the coding sequence becoming CAG TTG TTG CTG instead of CAG TTG CTG. The studies of Lecomte et al. (1988) indicated a high prevalence of hereditary elliptocytosis due to this mutation in populations of west Africa as well as in black people living in North America.
Boulanger et al. (1992) described fast screening methods for detection of this and the L260P mutation (182860.0001); the findings will be useful in studying the relationship between malaria resistance and the LEU154DUP mutation. Miraglia del Giudice et al. (1992) reported the same mutation in 2 women from southern Italy, Campania and Sicily; however, the associated haplotype was the same as that encountered in African and American blacks and in North Africans. It is assumed that the mutation was introduced from North Africa across the Sicilian channel and ultimately originated from the Benin-Togo area. This was the same migratory pathway followed by the Benin type hemoglobin S allele, which is also present in southern Italy.
This mutation was designated SER255PRO by Marchesi et al. (1987) and Sahr et al. (1989). For a time the numbering system used for SPTA1 was based on a sequence that lacked the first 6 residues.
Marchesi et al. (1987) and Sahr et al. (1989) found this substitution, which resulted from a TCC-to-CCC change in exon 6, in patients with elliptocytosis (EL2; 130600). This mutation is a Sp-alpha I/50-46a variant.
This mutation was designated ARG39SER by Lecomte et al. (1989). For a time the numbering system used for SPTA1 was based on a sequence that lacked the first 6 residues.
In the family of a 36-year-old man with hereditary pyropoikilocytosis (HPP; 266140), Lecomte et al. (1989) found a typical mild hereditary elliptocytosis (EL2; 130600) in the mother, 2 brothers, a sister, and 2 nieces. The proband had severe neonatal hemolytic anemia requiring exchange transfusions and a splenectomy at 1 year of age. Lecomte et al. (1989) demonstrated a G-to-T transversion in codon 39 (AGT for AGG), which changed the normal arginine to a serine in alpha-spectrin. This mutation, designated spectrin Clichy, is a Sp-alpha I/78 variant.
This mutation was designated GLY40VAL by Morle et al. (1989, 1990). For a time the numbering system used for SPTA1 was based on a sequence that lacked the first 6 residues.
Morle et al. (1989, 1990) found this substitution in a French Caucasian family with Sp-alpha I/74 hereditary elliptocytosis (EL2; 130600) defined on the basis of altered peptide maps following partial digestion of spectrin. The alpha-174 kD fragment is increased at the expense of the parent alpha-I 80 kD fragment. A GGT-to-GTT change in codon 40 (in exon 2) resulted in substitution of valine for glycine. This mutation was designated spectrin Culoz.
This mutation was designated LEU43PHE by Morle et al. (1989, 1990). For a time the numbering system used for SPTA1 was based on a sequence that lacked the first 6 residues.
Morle et al. (1989, 1990) found this mutation in a French Caucasian family with Sp-alpha I/74 type of hereditary elliptocytosis (EL2; 130600). The mutation, a CTT-to-TTT change in codon 43, was demonstrated by amplification of alpha-spectrin cDNA derived from reticulocyte mRNA. This mutation was designated spectrin Lyon.
In the kindred with autosomal recessive spherocytosis (SPH3; 270970) reported by Agre et al. (1986), Marchesi et al. (1989, 1989) identified a CGT-to-GAT change resulting in an ala970-to-asp (A970N) substitution in the alpha-II domain.
Boivin et al. (1993) searched for this mutation in patients with dominant or with what the authors termed 'non-dominant' spherocytosis, including 78 patients, 55 relatives, and 46 controls. They found that the mutation and the HS disease gene were located on different chromosomes and inherited independently of each other.
This mutation was designated ARG35TRP by Morle et al. (1989). For a time the numbering system used for SPTA1 was based on a sequence that lacked the first 6 residues.
Morle et al. (1989) described spectrin Tunis, an alpha-spectrin variant that causes asymptomatic hereditary elliptocytosis (EL2; 130600) in the heterozygous state. The variant was found in a white North African man and his mother. Morle et al. (1989) demonstrated that a C-to-T base substitution converted arginine-35 (CGG) to tryptophan (TGG). This mutation is a Sp-alpha I/78 variant.
In affected members of a kindred of Arab/Druze origin segregating elliptocytosis (EL2; 130600), Coetzer et al. (1991) identified a CGT-to-CTT change resulting in substitution of leucine for arginine at codon 28 of the SPTA1 gene. Coetzer et al. (1991) identified 3 other mutations in codon 28 (see 182860.0012, 182860.0013, 182860.0014). All the probands were heterozygous. All 4 point mutations abolished an AhaII restriction enzyme site which allowed verification of linkage of the mutation with elliptocytosis. The findings suggested that codon 28 is a hotspot for mutations and also indicated that arginine-28 is critical for the conformational stability and functional self-association of spectrin heterodimers. All 4 arg28 mutations are Sp-alpha I/74 variants.
In affected members of 2 unrelated white kindreds of English/European origin segregating for elliptocytosis (EL2; 130600), Coetzer et al. (1991) found a CGT-to-AGT mutation leading to substitution of serine for arginine at codon 28 of the SPTA1 gene. See 182860.0011.
Gallagher et al. (1991) found the same mutation in a patient with hereditary pyropoikilocytosis (HPP; 266140). The patient was heterozygous for a single structural variant of spectrin and possessed a second, uncharacterized defect, thus explaining the difference in phenotype from that in the patients with the same defect reported by Coetzer et al. (1991).
See 182860.0011. In affected members of 2 apparently unrelated white kindreds from New Zealand segregating for elliptocytosis (EL2; 130600), Coetzer et al. (1991) identified a CGT-to-TGT mutation in the SPTA1 gene that resulted in substitution of cysteine for arginine-28.
In an Italian child, Lorenzo et al. (1993) observed a de novo CGT-to-TGT mutation at codon 28 producing severe pyropoikilocytosis (HPP; 266140). The severity of the manifestations was thought to be accounted for by the occurrence, in trans to the alpha-28 mutation, of a polymorphism leading to a structural abnormality of the alpha-IV/alpha-V domain junction and with a low expression level, i.e., a so-called LE allele. The recurrent mutation strengthens the view that codon alpha-28 is a mutational 'hotspot.'
This mutation was originally reported by Garbarz et al. (1989, 1990) as ARG22HIS (R22H). For a time the numbering system used for SPTA1 was based on a sequence that lacked the first 6 residues.
In affected members of the French Caucasian family originally reported by Lecomte et al. (1987), Garbarz et al. (1989, 1990) found a CAT-to-CGT change in codon 22 in exon 2 of the SPTA1 gene (which encodes amino acids 3 to 82 of the alpha-I domain). In the family, 12 subjects in 4 generations had a disorder of the red cells varying from mild elliptocytosis to hemolytic elliptocytosis (EL2; 130600) to pyropoikilocytosis (HPP; 266140). In 8 of the 12 affected persons, heterozygosity for a spectrin alpha-I/74 kD defect was demonstrated by analysis of spectrin tryptic fragments. The defect resulted in decreased ability of the spectrin dimers to self-associate. Clinical severity correlated with amount of mutant spectrin and excess of spectrin dimer in the red cell membrane.
The R28H mutation was found by Baklouti et al. (1991) in a boy with severe elliptopoikilocytosis and in his clinically normal father. The severe expression in the son was attributable to the existence in trans of the alpha-V/41 polymorphism transmitted from the mother.
In an American black kindred and a black kindred from Ghana, Coetzer et al. (1991) identified a CGT-to-CAT mutation that resulted in substitution of histidine for arginine-28. See 182860.0011.
In 9 individuals from 5 unrelated families with hereditary elliptocytosis (EL2; 130600) or hereditary pyropoikilocytosis (HPP; 266140), including one of the original HPP probands reported by Zarkowsky et al. (1975), Gallagher et al. (1992) found the alpha-I/46-50a peptide after limited tryptic digestion of spectrin. Further studies identified a point mutation causing the replacement of a highly conserved leucine residue by proline at position 207 in the alpha-spectrin chain, a site 51 residues to the amino-terminal side of the abnormal proteolytic cleavage site. Dalla Venezia et al. (1993) found the leu207-to-pro mutation in a Moroccan family in both homozygous and heterozygous states. The mutated allele carried, in cis, the common alpha-V/41 polymorphism, which is associated with a low expression level. Dalla Venezia et al. (1993) suggested that the cis combination of an HE mutation and the alpha-V/41 polymorphism accounts for the low expression of the abnormal allele in the heterozygous state.
In the original family of Zarkowsky et al. (1975), the L207P mutation was in compound heterozygous state with an SPTA1 allele associated with a defect in alpha-spectrin production. By analysis of reticulocyte alpha-spectrin cDNA from 1 of the original HPP patients, Costa et al. (2005) identified a G-to-A transition (182860.0024) at position +5 of the donor splice site of intron 22 of the SPTA1 gene, resulting in insertion of intronic fragments and an in-frame premature termination codon. Following gene transfer of the IVS22+5 mutation into tissue culture cells, there was complete absence of normally spliced SPTA1 gene transcript.
In a case of hereditary pyropoikilocytosis (HPP; 266140), Gallagher et al. (1991) found substitution of arginine for lysine at residue 48 of alpha-spectrin. HPP is a severe hemolytic anemia characterized by abnormal sensitivity of red blood cells to heat and erythrocyte morphology similar to that seen in thermal burns. The genetics of HPP usually falls into 1 of 3 categories: (1) the patients may be homozygous for a structural variant of spectrin; (2) they may be compound heterozygous for 2 different structural variants of spectrin; or (3) they may be heterozygous for a single structural variant of spectrin and possess a second, uncharacterized defect. The patient with the lys48-to-arg mutation was of the third type. This mutation is a Sp-alpha I/74 variant.
Alloisio et al. (1992) found an alpha-spectrin variant associated in the heterozygous state with asymptomatic elliptocytosis (EL2; 130600) and a minimal defect in spectrin dimer self-association in a Tunisian family. The responsible mutation was found to be a GAC-to-GAA transversion resulting in substitution of glutamic acid for aspartic acid at codon 791. As in most alpha-spectrin variants associated with elliptocytosis, the change altered helix 3 of the proposed triple helical model of spectrin structure. This change was the most distant from the N terminus of alpha-spectrin yet found in variants associated with elliptocytosis. This mutation, designated spectrin Jendouba, is a Sp-alpha II/31 variant.
In an Algerian family, Alloisio et al. (1988) identified a new alpha-spectrin variant, spectrin Oran, that in the homozygous state caused severe elliptocytosis (EL2; 130600). All but 2 obligate heterozygotes were clinically normal and had normal hematologic findings; one of the exceptions 'presented some degree of anisocytosis with rare elliptocytes' and the other had findings consistent with heterozygosity for a form of alpha-thalassemia affecting 10% of Algerian people. As indicated in the report of Alloisio et al. (1993), several members of the family who were homozygotes required transfusion, and partial splenectomy was performed at the age of 8 months in 1 of these. Alloisio et al. (1993) demonstrated loss of amino acids 822 to 862 (helix 2 of repeating segment alpha-8). The ultimate genetic lesion was found to be a G-to-A transition at intronic position -1 in the acceptor splice site of intron 17 resulting in skipping of exon 18. The substitution also created an acceptor splice site 1 basepair downstream, but the latter was used only to a minor extent. This mutation is a Sp-alpha II/21 variant.
In a 3-generation family with hereditary elliptocytosis (EL2; 130600) and pyropoikilocytosis (HPP; 266140), Hassoun et al. (1994) found a truncated alpha-spectrin protein. They showed, furthermore, that the SPTA1 gene had been disrupted by a mobile element resulting in exon skipping. The element caused duplication of the insertion site and was terminated by a long poly(A) tail downstream of multiple consensus polyadenylation signals. Southern blot analysis of human genomic DNA, using this element as probe, revealed 1 to 3 copies per individual. The element had no homology to any previously reported sequence and therefore appeared to be a member of a novel family of mobile elements. This mutation is a Sp-alpha I/50-46a variant.
Ostertag et al. (2003) showed that the sequence change observed by Hassoun et al. (1994) was the result of an SVA-mediated transduction event. (Shen et al. (1994) used the term 'SVA' (SINE-R, VNTR, and Alu) to describe such a 'composite retroposon.') Ostertag et al. (2003) showed that the de novo insertion into the alpha-spectrin gene was caused by an SVA-mediated transduction.
Lecomte et al. (1990) reported the case of a patient with severe poikilocytic anemia, the child of apparently unrelated parents, both from Guadeloupe in the French West Indies. The baby had severe hemolytic anemia requiring frequent blood transfusions. Partial splenectomy was performed at age 3, but complete splenectomy was necessary 2 years later. Thereafter the propositus experienced a compensated hemolysis. Blood smears showed marked poikilocytosis with spherocytes, microspherocytes, and a few elliptocytes as observed in hereditary pyropoikilocytosis (HPP; 266140). In the patient reported by Lecomte et al. (1990), Fournier et al. (1997) identified a splicing mutation of the SPTA1 gene: a T-to-G transversion at nucleotide position -13 upstream of the 3-prime acceptor splice site of exon 20. This polypyrimidine tract mutation created a new acceptor site, AT-to-AG, and led to the production of 2 novel mRNAs. One mRNA contained a 12-nucleotide intronic insertion upstream of exon 20. This insertion introduced a termination codon into the reading frame and was predicted to encode a truncated protein that lacked the nucleation site and thus could not be assembled in the membrane. In the other mRNA, there was in-frame skipping of exon 20, predicting a truncated alpha-spectrin chain. The homozygous propositus had only truncated (277 kD) alpha-spectrin chains in his erythrocyte membranes. His heterozygous parents were clinically and biochemically normal. This allele was identified in 3% of asymptomatic individuals from Benin, Africa, when a new MwoI restriction site was used for identification of heterozygosity. This mutation, designated spectrin St Claude, is a Sp-alpha II/47 variant.
Burke et al. (1998) found the same mutation in the SPTA1 gene in a South African kindred with pyropoikilocytosis (266140), previously reported by Coetzer and Zail (1982) and Zail and Coetzer (1984). The kindred was of Afrikaner origin. The parents were apparently unrelated. Because the probands were homozygous for the mutation, the parents were obligate heterozygotes. Partial spectrin deficiency in a proband's erythrocyte membranes resulted from a spectrin-ankyrin binding defect and destabilized the lipid bilayer, causing spherocytes. The reduced membrane spectrin content in concert with the milder dimer self-association defect further weakened the membrane skeleton and allowed deformation of the erythrocytes into elliptocytes and poikilocytes. The observations illustrated how a single point mutation in the alpha-spectrin gene impairs functions of both the alpha- and the beta-spectrin proteins, resulting in qualitative and quantitative membrane abnormalities. The variant was also referred to spectrin Johannesburg.
Wichterle et al. (1996) studied a patient with severe spherocytic hemolytic anemia (SPH3; 270970) without a family history of spherocytosis. Analysis of the patient's erythrocyte membrane proteins revealed spectrin deficiency and a truncated alpha-spectrin protein. They determined that the patient was a compound heterozygote with 2 mutations in the alpha-spectrin gene. The mutation in the paternal allele, designated alpha-spectrin-Prague, was an A-to-G transition in the penultimate position of intron 36 that led to skipping of exon 37, frameshift, and production of the truncated alpha-spectrin protein. The maternal allele, designated alpha-spectrin-Lepra, contained a C-to-T transition at position -99 of intron 30 (182860.0023). This mutation enhanced an alternative acceptor splice site 70 nucleotides upstream from the regular site. The alternative splicing caused a frameshift and premature termination of translation leading to a significant decrease in alpha-spectrin production. The spectrin-Lepra mutation was linked to a spectrin alpha-IIa marker that was found to be associated with recessive or nondominant spectrin-deficient hereditary spherocytosis in approximately 50% of studied families. Wichterle et al. (1996) concluded that the spectrin-Lepra mutation combined in trans with the alpha-Prague mutation was responsible for the severe hemolytic anemia in the proband. They suggested, furthermore, that the spectrin-Lepra allele may frequently be involved in the pathogenesis of recessive or nondominant spectrin-deficient hereditary spherocytosis.
For discussion of the C-to-T transition at position -99 of the SPTA1 gene, designated alpha-spectrin-Lepra, that was found in compound heterozygous state in a patient with severe spherocytic hemolytic anemia (SPH3; 270970) by Wichterle et al. (1996), see 182860.0022.
For discussion of the G-to-A transition at position +5 of the donor splice site of intron 22 of the SPTA1 gene that was found in compound heterozygous state in affected members of a family with hereditary pyropoikilocytosis (HPP; 266140), by Costa et al. (2005), see 182860.0016.
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