HGNC Approved Gene Symbol: HBD
SNOMEDCT: 16427007, 62074008;
Cytogenetic location: 11p15.4 Genomic coordinates (GRCh38): 11:5,232,838-5,234,483 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 11p15.4 | Thalassemia due to Hb Lepore | 3 | ||
| Thalassemia, delta- | 3 |
The delta locus determines the delta, or nonalpha, chain of hemoglobin A(2) (alpha-2/delta-2). Jeffreys (1979) found an example of a restriction enzyme variant in a DNA intervening sequence of the delta-globin gene. Spritz et al. (1980) could not 'identify unambiguously the structural basis of the low level of expression characteristic of the delta-globin gene.' They discussed the basis for evolution of duplicate adult beta-type genes. Petes (1982) suggested that some of the structural variants of the delta chain may be the consequence of a nonreciprocal transfer of information from the beta-globin gene to the delta-globin gene by a process termed 'intrachromosomal gene conversion' (Klein and Petes, 1981). Losekoot et al. (1989) described a patient who was a compound heterozygote for delta-0-thalassemia and for a deletion type of thalassemia. By amplifying the delta gene by PCR and sequencing it, they showed that the mutant gene had an insertion of an extra nucleotide at the third position of codon 91 of the second exon which gave rise to a premature stop codon at position 94. They presented a model to explain the insertion, namely, the formation of a hairpin loop by quasipalindromic sequences.
Carver and Kutlar (1995) listed 27 delta-chain variants as of the beginning of 1995.
The first-to-be discovered fusion hemoglobin, hemoglobin Lepore (which has several forms) has HBD sequence at the 5-prime end and HBB (141900) sequence at the 3-prime end. See, for example, Hb Lepore (Baltimore) (142000.0019) and Hb Lepore (Boston) (142000.0020). Formed by nonhomologous pairing and unequal crossing over, the fusion protein resulting from the complementary event is referred to as Hb anti-Lepore and has HBB sequence at the 5-prime end and HBD sequence at the 3-prime end; see, for example, hemoglobin Lincoln Park (141900.0157). Carver and Kutlar (1995) listed 10 fusion hemoglobins that had been described by the beginning of 1995.
De Angioletti et al. (2002) characterized mutations and haplotypes of the HBD gene in 2 regions of southern Italy. They screened approximately 10,000 students in Basilicata and found 53 carriers of HBD variants in 43 unrelated families; in Campania, patients were ascertained through a routine thalassemia counseling service. They found 6 novel mutations and stated that 46 HBD mutations had been previously characterized, of which 30 were from the Mediterranean area (Huisman and Carver, 1998).
See Horton et al. (1961), Ball et al. (1966), Vella and Graham (1969), and Lehmann et al. (1985). Schiliro et al. (1991) found this variant, which had previously been described almost exclusively in populations of African origin, in 5 members of 2 unrelated families in Sicily. This was taken as further evidence of the genetic admixture between African and Sicilian populations.
Hb A(2)-prime is characterized by substitution of a glycine by an arginine residue at position 16. Horton et al. (1961) found the carrier frequency of the variant to be 1% to 3% in the black population of the southeastern United States and Jenkins and Dunn (1981) found a frequency of up to 9% in South African blacks. It occurs in about 9.2% in the Herero population belonging to the South African Bantu-speaking blacks from Namibia (Spurdle et al., 1994). In an epidemiologic study of hemoglobin variants in the Dogon country of Mali, Bennani et al. (2003) identified this Hb A(2) variant and characterized the associated haplotype of the beta-globin gene cluster. In all cases it was linked to a unique haplotype which was the same as that linked to Hb A(2)-prime in the Herero population. Although the unique origin of this mutation in Africa was considered a possibility, a recurrent mutational event could not be excluded because the linked beta-cluster haplotype was 1 of the 2 major haplotypes found in all African populations.
Jones et al. (1967) found this mutation in compound heterozygous state with hemoglobin A(2) Flatbush (142000.0007).
XIII Meeting Gruppo di Studio Dell 'Entrocita': Torino, 12 June, 1977.
See De Jong and Bernini (1968).
In an Asiatic Indian family, Salkie et al. (1982) observed a delta variant hemoglobin with increased oxygen affinity. Asparagine was substituted for aspartic acid at delta 99. The same substitution occurs in the beta chain in Hb Kempsey, which, like other substitutions at beta 99, is accompanied by erythrocytosis due to its increased oxygen affinity.
See Sharma et al. (1975).
See Williamson et al. (1984).
See Lee and Huisman (1964) and Jones et al. (1967).
See Fujita et al. (1985).
See Lie-Injo et al. (1971).
See Romero Garcia et al. (1983).
See Sharma et al. (1974).
See Ranney et al. (1969) and De Jong and Went (1974). Schiliro et al. (1991) found this rare variant in 2 members of a family in Sicily. They interpreted their findings of 6 rare hemoglobin variants in Sicily as reflecting the fact that Sicily was at the crossroads of the world for thousands of years.
De Angioletti et al. (2002) found this variant in 11 families from Basilicata, southern Italy, associated with haplotype I. Because all 11 families lived in a restricted area extending from the Ionian coast for 15 kilometers along the Angri and Sinni Rivers, De Angioletti et al. (2002) suggested a founder effect.
See Rieder et al. (1976).
See Jones et al. (1966).
See Brennan et al. (1984).
Substitution of methionine for valine as amino acid 98 in the delta chain of hemoglobin A(2) was found by Codrington et al. (1989) when they studied an 85-year-old black male who had an allele for hereditary persistence of fetal hemoglobin on 1 chromosome and a suspected 'delta-thalassemia' on the other. Sequence analysis of amplified DNA showed the GTG-to-ATG mutation of codon 98. Thus, the delta-thalassemia was caused by the presence of a Hb A(2) variant that was unstable to an extent similar to Hb Koln, its beta-chain counterpart. The proband had a very low level of hemoglobin A(2).
See Ohba et al. (1985).
See Juricic et al. (1983).
Delta-beta fusion (delta 50 to beta 86) is the molecular lesion. See Ostertag and Smith (1969) and Efremov et al. (1976). Among 5 chromosomes carrying the Hb Lepore (Baltimore) hybrid gene, Lanclos et al. (1987) found a characteristic haplotype.
Delta-beta fusion (delta 87 to beta 116) is the molecular lesion. Different hemoglobins Lepore show evidence that the crossover occurred at different sites: e.g., Hb Lepore (Washington) has the shift-over somewhere between amino acids at 87 and 116 (Labie et al., 1966). (It is impossible to position it more precisely because the delta and beta chains are identical between these residues.) Among 44 chromosomes carrying the Hb Lepore (Washington) hybrid gene, Lanclos et al. (1987) found 2 and possibly 3 different haplotypes. See Baglioni (1962), Fessas et al. (1962), Curtain (1964), and Ahern et al. (1972). Using maternal blood as a source for fetal cells in 3 pregnancies at risk for beta-thalassemia/hemoglobin Lepore disease, Camaschella et al. (1990) made a molecular diagnosis of hemoglobin Lepore-Boston in the fetus. Taking advantage of the PCR method for amplifying Lepore-specific DNA fragments in families in which Hb Lepore was inherited on the paternal side, they demonstrated in 2 cases and excluded in 1 the presence of this hemoglobinopathy in the fetus through the study of DNA from the maternal blood. This is one of the first instances of prenatal diagnosis by study of fetal cells in the maternal circulation. Fioretti et al. (1992) identified a hybrid delta-beta-globin gene in 40 families living in Abruzzo and Campania, which are on the east and west coast of Italy, respectively. In all cases the gene was of the Lepore-Boston type: it had the delta-globin sequence up to exon 2 codon 87 and had the beta-globin sequence from nucleotide 8 of IVS2. Between these 2 ends, the gene had 58 bp in common with the delta- and beta-globin genes. Fioretti et al. (1992) found that 12 of 12 genes from Abruzzo were of 1 haplotype, which was present in only 8 of 31 genes from Campania. The other Campania genes were all of another haplotype. DNA sequencing of homozygous subjects who showed the 'Abruzzo haplotype' had G at nucleotide 74 of IVS2, whereas those of the alternative haplotype had a T at that site. The geographic pattern as well as the molecular characteristics suggested to Fioretti et al. (1992) that Hb Lepore-Boston had had recurrent and multicentric origins.
Delta-beta fusion (delta 22 to beta 50) is the molecular lesion. Several hemoglobins Lepore have been shown to differ in the position of the crossover between the delta and beta chains (Curtain, 1964). See Neeb et al. (1961), Barnabas and Muller (1962), and Baglioni (1962).
Edison et al. (2005) discussed the clinical picture resulting from heterozygosity for hemoglobin E beta-thalassemia (141900.0071) and Hb Lepore (Hollandia) on the basis of a case in India.
A delta-beta-delta hybrid nonalpha globin chain, presumably the result of a double crossover in the nonalpha-globin region, is the molecular lesion. One crossover apparently occurred between the codons for residues 12 and 22 and the second between the codons for residues 50 and 86 of the beta globin chain. See Adams et al. (1981, 1982).
Hb Knossos (HBB, ala27-to-ser, 141900.0149) is a silent beta-plus thalassemia variant, which was first described in a Greek family. Heterozygotes from the Mediterranean area show low Hb A2 levels and homozygotes show absence of Hb A2. In contrast, heterozygotes in a family from the French West Indies had high Hb A2 levels typical of classic beta-thalassemia carriers. Loudianos et al. (1991) found a single nucleotide deletion at codon 59 (AAG to AG) of the HBD gene, producing a frameshift which resulted in the production of a stop codon at position 60.
Loudianos et al. (1991) found a C-to-T mutation resulting in substitution of cysteine (TGC) for arginine (CGC) at position 116 of the delta chain. Hb A2-Coburg (142000.0005) has mutation at the same nucleotide. In a study of a Greek Cypriot family suspected of having delta-thalassemia, Trifillis et al. (1991) found this same mutation.
In a female of Italian parentage living in Australia, Leung et al. (1991) described a substitution of aspartic acid-47 by valine in the delta-globin chain.
Oggiano et al. (1987) described a family of northern Sardinian descent in which the propositus was affected by thalassemia major, resulting from compound heterozygosity for the codon 39 missense mutation and the beta+ IVS2 nucleotide 745 mutation, and in which all heterozygotes for the latter mutation had normal HbA-2 levels. Moi et al. (1992) found that the delta-thalassemia gene in cis to the latter mutation showed a G-to-A change 69 nucleotides downstream to the poly(A) addition site. The normal G at position 69 is part of a GATA box that is a binding site for the GATA-1 protein. A DNA fragment containing the GATA motif with the G-to-A substitution at position +69 had increased binding affinity for erythroid-specific DNA binding protein(s) as compared with the wildtype sequence.
In 3 healthy Japanese individuals with an abnormal hemoglobin chromatographic pattern, Harano et al. (1991) found that the valine residue at the first position of the delta chain was replaced by an alanine residue.
This variant was numbered based on the first amino acid of the mature protein. In the gene-based system of counting, this variant is VAL2ALA.
Renda et al. (1992) demonstrated homozygosity for a G-to-T transversion at the first nucleotide of codon 27 of the delta-globin gene in a Sicilian woman. This mutation had first been demonstrated in Sardinia by Moi et al. (1988). In an attempt to identify mutations that might be the basis of delta-thalassemia, Trifillis et al. (1991) amplified by PCR the HBD region from 3 Greek Cypriot families and determined the DNA sequence. Four novel mutations were identified. One of these was a G-to-T transversion at codon 27 resulting in an alanine to serine change. The G-to-T change presumably activates a cryptic splice site resulting in aberrant transcript processing.
De Angioletti et al. (2002) found this variant in 42 of 63 families in 2 regions of southern Italy.
Loudianos et al. (1992) found that an individual of southern Italian descent was heterozygous for Sicilian delta-beta-thalassemia and for delta-thalassemia. Direct sequencing of the amplified delta-globin gene demonstrated that the allele responsible for delta-thalassemia carried a G-to-C substitution of the last nucleotide of exon 1 which most likely adversely affected pre-mRNA splicing. An identical G-to-C mutation predicting substitution of threonine for arginine at codon 30 has been identified in the beta-globin chain, where it results in beta-thalassemia because of a marked (98%) reduction of mRNA splicing at the 5-prime splice site of IVS1 of the beta-globin gene (141900.0144). Loudianos et al. (1992) cited 2 other examples of identical mutations observed in the beta- and delta-globin genes. They suggested that such might occur in these 2 linked genes either as independent mutations or as the result of gene conversion events.
In 3 unrelated Japanese patients homozygous for delta-thalassemia, Matsuda et al. (1992) detected a T-to-C substitution at position -77 of the HBD gene. The mutation is located within the inverted binding motif of GATA-1 (305371), an erythroid cell-specific transcription factor. They found that GATA-1 did not bind to an oligonucleotide with the mutation at position -77.
In a Greek Cypriot family suspected of having delta-thalassemia, Trifillis et al. (1991) found a T-to-C transition at codon 141 converting leucine to proline.
In a Greek Cypriot family with delta-thalassemia, Trifillis et al. (1991) found a change from AG to GG in the last 2 nucleotides of the 3-prime acceptor site of IVS-2 of the HBD gene. The change resulted in total absence of hemoglobin Hb A2. The same change in the beta-globin gene results in a beta-0-thalassemia phenotype.
Delta-chain abnormal hemoglobins with neutral substitutions are difficult to detect unless the amino acid replacement causes the variant to have some special properties, such as Hb A(2) Niigata (142000.0027), which is acetylated, or Hb A(2) Wrens (142000.0016), which is unstable. Molchanova et al. (1993) discovered Hb A(2) Grovetown accidentally during the course of a testing program for sickle cell anemia using isoelectric focusing (IEF). The change was found to be a C-to-G mutation converting codon 75 from CTG (leu) to GTG (val).
In a southern Italian family in which the propositus has a thalassemia-like hematologic disorder, Loudianos et al. (1993) found a variant of hemoglobin A(2) in combination with heterozygous beta-thalassemia. The variant, named Hb-Puglia after the birthplace of the propositus, was found to be due to a G-to-C transversion at the third position of codon 26 of the HBD gene, resulting in substitution of aspartic acid for glutamic acid. In spite of the lack of modification in the charge of the molecule resulting from the substitution, the variant was resolved from the normal Hb A(2) by both cellulose acetate electrophoresis and isoelectric focusing.
In 3 subjects from the same Italian family, Gasperini et al. (1994) described a G-to-A transition in codon 37 of the HBD gene, resulting in the production of an 'in phase' termination codon: (TGG) trp to (TAG) stop. The subjects with this change showed normal red cell indices and low hemoglobin A2. Gasperini et al. (1994) indicated that this was the first nonsense mutation identified in the delta-globin gene. Characterization of the lesion should be an aid in identification of double heterozygotes for delta- and beta-thalassemia who, because of normal Hb A2 levels, may be missed in carrier screening programs for beta-thalassemia.
During a beta-thalassemia screening program in Sardinia, Galanello et al. (1994) found a variant Hb A(2) due to a TGT-to-GGT transversion that changed codon 93 from cysteine to glycine.
In a Greek family, Papadakis et al. (1995) found a new delta-chain variant, producing altered electrophoretic mobility of hemoglobin A(2). Direct sequencing of amplified DNA revealed a change in codon 43 from GAG (glu) to GGG (gly).
In a family from west Sicily, De Angioletti et al. (2002) detected an abnormal hemoglobin by cation exchange high performance liquid chromatography. The mutation was a substitution of CAT (his) by CGT (arg) at codon 146 of the HBD gene. Two carriers had reduced levels of normal hemoglobin A2 but comparable levels of the hemoglobin A2 variant. The new variant was thought to have the same characteristics as Hb Cochin-Port Royal which is the same mutation at the same position in the HBB gene, his146 to arg (141900.0051); that variant is stable but has a 75% reduction of the Bohr effect.
In 1 family from the Basilicata region of southern Italy, De Angioletti et al. (2002) found a C-to-A transversion at position 238 of the HBD genomic DNA that resulted in a pro37-to-his (P37H) substitution. Hemoglobin A2 was 1.3% in the carrier, and mutant hemoglobin A2 was 0.6%, approximately 50% of the expected value.
In 1 family form the Campania region of southern Italy, De Angioletti et al. (2002) found a C-to-A transversion at position 302 of the HBD genomic DNA that resulted in an asn58-to-lys (N58K) substitution. Mutant hemoglobin A2 was extremely low in the 2 carriers, corresponding to approximately 15% of the total hemoglobin A2.
In a family from the Basilicata region of southern Italy, De Angioletti et al. (2002) found a C-to-G transversion at position 393 of the HBD genomic DNA that resulted in a leu89-to-val (L89V) substitution. This mutation appeared to have arisen in the carrier, as the parents did not present the allele, paternity having been established by HLA typing and RFLP haplotypes.
In 1 family from the Campania region of southern Italy, De Angioletti et al. (2002) found a G-to-T transversion at position 443 of the HBD genomic DNA that resulted in an arg-to-ser change at codon 105 (R105S).
In 1 family frpm the Basilicata region of southern Italy, De Angioletti et al. (2002) found a T-to-A transversion at position 6 of the consensus sequence of the donor site of intron 2 of the HBD gene. The 2 carriers showed mild Hb A2 decrease with normal iron metabolism. Hb A2 values indicated that the mutation most likely affects splicing efficiency of intron 2.
In 1 family from the Campania region of southern Italy, De Angioletti et al. (2002) found an A-to-T transversion at position -126 of the HBD gene. This mutation was located within the GATA motif and was thought to abolish GATA1 binding and lead to a null allele.
In a 2-year-old girl originally from Ninive, Iraq, who presented with microcytic anemia and minimal growth retardation, Frischknecht and Dutly (2005) identified heterozygosity for a GTG-to-GCG transition at codon 133 of the HBD gene. This HBD mutation is analogous to the beta-chain mutation Hb Renert (val133 to ala; 141900.0496).
In a 40-year-old Italian with typical but mild thalassemic hematologic indices, Frischknecht and Dutly (2005) found double heterozygosity for 2 thalassemia mutations. One was the common IVS1+6 (T-to-C) of the HBB gene (141900.0360); the other was a -31A-G transition within the TATA box of the HBD gene. This mutation is analogous to the -31A-G mutation in the HBB gene (141900.0376). Simultaneous heterozygosity for beta-thalassemia and delta-thalassemia is a frequent and well-known complication in beta-thal carrier detection (see epidemiologic studies in southern Italy by De Angioletti et al. (2002) that showed a wide variety of HBD gene mutations that came to light because of their association with HBB mutations in cases of beta-thalassemia).
HEMOGLOBIN DELTA CHAIN TETRAMER. Not yet proven to be a tetramer. See Huehns (1962) and Huehns et al. (1962).
HEMOGLOBIN LEPORE (CYPRUS). Delta-beta fusion. See Beaven et al. (1964).
HEMOGLOBIN LEPORE (THE BRONX). Delta-beta fusion. The N-terminal portion is coded by a 5-prime part of the delta gene and the C-terminal portion by a 3-prime part of the beta gene. See Ranney and Jacobs (1964) and Ramirez et al. (1979).
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