* 301300

DELTA-AMINOLEVULINATE SYNTHASE 2; ALAS2


Alternative titles; symbols

ALAS, ERYTHROID; ALASE
5-AMINOLEVULINATE SYNTHASE, ERYTHROID-SPECIFIC


HGNC Approved Gene Symbol: ALAS2

Cytogenetic location: Xp11.21     Genomic coordinates (GRCh38): X:55,009,055-55,030,977 (from NCBI)


Gene-Phenotype Relationships
Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
Xp11.21 Anemia, sideroblastic, 1 300751 XLR 3
Protoporphyria, erythropoietic, X-linked 300752 XL 3

TEXT

Description

Delta-aminolevulinate synthase (ALAS; EC 2.3.1.27) catalyzes the first committed step of heme biosynthesis, which is the synthesis of 5-aminolevulinic acid, the first common precursor of all tetrapyrroles, from glycine and succinyl-coenzyme A (sCoA) in a pyridoxal 5-phosphate (PLP)-dependent manner (Astner et al., 2005). Two forms of ALAS exist in humans: a housekeeping form encoded by the ALAS1 gene (125290), and an erythroid tissue-specific form encoded by the ALAS2 gene (Bishop et al., 1990).


Cloning and Expression

Astrin and Bishop (1989) isolated the ALAS2 gene from an erythroid human fetal liver library. ALAS2 appeared to be expressed only in erythroid cells.


Gene Structure

Surinya et al. (1998) determined that the ALAS2 gene spans about 35 kb and contains 11 exons. An erythroid-specific enhancer in intron 8 contains GATA and CACCC boxes that are conserved in mouse and canine Alas2.


Mapping

Benoff and Skoultchi (1977) presented 3 lines of evidence that a locus on the X chromosome in the mouse controls hemoglobin synthesis. Following Ohno's law, one would expect the same locus to exist in man.

Benoff et al. (1978) identified in the mouse an X-linked locus that inhibits hemoglobin production by inhibiting inducible heme biosynthesis, probably at the step catalyzed by delta-aminolevulinic acid synthetase. Close linkage to the Xg locus was excluded by Elves et al. (1966).

Astrin et al. (1987) mapped the ALAS1 gene to chromosome 3, excluding it as a candidate gene for X-linked hypochromic anemia. Later, however, Astrin and Bishop (1989) isolated a second ALAS gene, ALAS2, and by Southern blot analysis of DNAs from somatic cell hybrids, assigned it to the X chromosome. Also see Bishop et al. (1990).

By Southern analysis of a mouse/human hybrid cell panel and by in situ hybridization, Cox et al. (1990) mapped the ALAS2 gene to chromosome Xp21-q21, with the most likely location being on band Xp11.2.

By analysis of DNA from hybrid clones containing translocations in the region Xp11.21-q21.3, Cotter et al. (1992) achieved finer localization of the ALAS2 gene with respect to other loci and breakpoints within this region. They localized the ALAS2 gene to subregion Xp11.21. Cox et al. (1992) identified a highly polymorphic marker, a compound dinucleotide repeat, within intron 7 of the ALAS2 gene and used it to confirm the localization of ALAS2 in the multipoint linkage map of the X chromosome. No recombination was observed between ALAS2 and the centromere marker DXZ1. No recombination was found with DXS14. Since Raskind et al. (1991) excluded linkage of DXS14 and X-linked sideroblastic anemia with spinocerebellar ataxia within 5 to 10 cM, one can probably conclude that there are at least 2 loci on the X chromosome determining sideroblastic anemia. One locus may be located on the proximal portion of Xq.

In the course of high-resolution comparative mapping of the proximal region of the mouse X chromosome, Blair et al. (1995) demonstrated the location of the Alas2 gene relative to others.


Gene Function

Using a reporter gene assay, Surinya et al. (1998) showed that intron 8 of the ALAS2 gene harbored strong orientation-dependent erythroid-specific enhancer activity. In vitro assays showed that GATA1 (305371) and SP1 (189906) bound the GATA and CACCC boxes within this region, respectively.

Han et al. (2006) showed that histone deacetylase (HDAC; see 601241) inhibitors increased ALAS2 expression in a human erythroid cell line. Increased ALAS2 expression was concurrent with increased acetylation of histone H4 (see 602822) at the ALAS2 promoter. Histone acetyltransferase p300 (EP300; 602700) bound the ALAS2 promoter, and overexpression of p300 increased promoter reporter expression and endogenous ALAS2 mRNA levels. The GATA1 and SP1 sites at the ALAS2 promoter synergistically contributed to p300-mediated ALAS2 activation.


Biochemical Features

Astner et al. (2005) determined the crystal structure of homodimeric Alas from Rhodobacter capsulatus, which shares 49% sequence identity with human ALAS. Mutations in the ALAS gene resulting in X-linked sideroblastic anemia were predicted to obstruct substrate binding, disrupt the dimer interface, or hamper proper folding (see, e.g., 301300.0002-301300.0005). The findings provided explanations for potential responsiveness to pyridoxine treatment in some cases.


Molecular Genetics

Sideroblastic Anemia 1, X-Linked

Aoki et al. (1973) found deficiency of delta-aminolevulinic acid synthetase in the red cells of patients with sideroblastic anemia-1 (SIDBA1; 300751), some of whom were males with congenital anemia which in some responded to treatment with vitamin B6.

In a 30-year-old Chinese male with a pyridoxine-responsive form of X-linked sideroblastic anemia, Cotter et al. (1992) identified a mutation in the ALAS2 gene (301300.0001).

Cotter et al. (1995) described a previously unaffected 81-year-old woman in whom microcytic sideroblastic anemia developed. She was found to be heterozygous for a point mutation of the ALAS2 gene (301300.0005). The initial diagnosis was myelodysplastic syndrome, but the recognition of the X-linked congenital sideroblastic anemia allowed successful treatment with pyridoxine. There is evidence from other sources that skewed lyonization can be an acquired pattern. In the study of peripheral blood leukocytes by Busque et al. (1996), the incidence of skewing was 1.9% in neonates, 4.5% in women who were 28 to 32 years old, and 22.7% in women who were 60 years of age or older. Cazzola and Bergamaschi (1998) estimated that in 30 to 40% of elderly women, hematopoietic cells (erythroid cells, granulocytic cells, monocytes, and megakaryocytes) have more than 90% expression of 1 parental X chromosome. Puck and Willard (1998) reviewed mechanisms for a skewed pattern with a diagram of 3 different mechanisms.

In each of 4 unrelated males with X-linked sideroblastic anemia, Cotter et al. (1999) identified new mutations: 647T-C, 1283C-T, 1395G-A, and 1406C-T predicting amino acid substitutions tyr199 to his (Y199H; 301300.0017), arg411 to cys (R411C; 301300.0008), arg448 to gln (R448Q), and arg452 to cys (R452C; 301300.0018), respectively. All probands were clinically pyridoxine-responsive. The Y199H mutation was demonstrated to be the first de novo XLSA mutation, having occurred in a gamete of the proband's maternal grandfather. In 18 unrelated XLSA hemizygotes, Cotter et al. (1999) found a significantly higher frequency of coinheritance of the hereditary hemochromatosis HFE mutant allele C282Y (235200.0001) than found in the normal population. One proband with the Y199H mutation with severe and early iron loading was homozygous for C282Y.

In an 81-year-old man who developed sideroblastic anemia while undergoing hemodialysis, Furuyama et al. (2003) identified heterozygosity for an asp159-to-asn change in the ALAS2 gene (D159N; 301300.0012).

Erythropoietic Protoporphyria, X-Linked

In 8 families with X-linked dominant erythropoietic protoporphyria (XLEPP; 300752), Whatley et al. (2008) identified 2 deletion mutations in exon 11 of the ALAS2 gene (301300.0015 and 301300.0016). The mutations were not found in 129 unrelated patients with other forms of erythropoietic protoporphyria or 100 normal chromosomes. The data of Whatley et al. (2008) demonstrated that disruption of the C-terminal region of ALAS2 leads to the production of protoporphyrin in excess of the amount required for hemoglobinization and in quantities sufficient to cause photosensitivity and liver damage, in spite of normal ferrochelatase (FECH; 612386) activity.

In 4 unrelated girls with X-linked dominant erythropoietic protoporphyria, Ducamp et al. (2013) identified 3 different heterozygous mutations in the ALAS2 gene. One was recurrent (delAGTG; 301300.0015) and the other 2 were novel (301300.0019 and 301300.0020). All occurred in the last exon of the ALAS2 gene, and all were shown in vitro to result in increased ALAS2 catalytic activity, consistent with a gain of function. All 4 girls presented in early childhood with severe photosensitivity associated with increased erythrocyte zinc- and metal-free protoporphyrin. Two had elevated liver enzymes, 1 had gallstones, and most had iron deficiency. The mother of 1 child was mildly affected and was shown to be somatic and germline mosaic for the mutation. By generating a series of ALAS2 variants, Ducamp et al. (2013) found that the 'gain-of-function domain' contains a minimum of 33 amino acids between residues 544 and 576 in the C terminus of the protein.


ALLELIC VARIANTS ( 20 Selected Examples):

.0001 ANEMIA, SIDEROBLASTIC, 1

ALAS2, ILE471ASN
  
RCV000011214

In a 30-year-old Chinese male with a pyridoxine-responsive form of X-linked sideroblastic anemia-1 (SIDBA1; 300751), Cotter et al. (1992) identified a T-to-A transition in codon 471 in a highly conserved region of exon 9 of the ALAS gene, resulting in an ile-to-asn substitution. The mutation interrupted contiguous hydrophobic residues and was predicted to transform a region of beta-sheet structure to a random-coil structure. Prokaryotic expression of the normal and mutant cDNAs showed that the mutant construct expressed low levels of enzymatic activity that required higher concentrations of pyridoxal 5-prime-phosphate to achieve maximal activation than did the normal enzyme. The amino acid substitution occurred in the exon containing the putative pyridoxal 5-prime-phosphate binding site. To identify the mutation, Cotter et al. (1992) amplified and sequenced the 11 exonic coding regions of the ALAS gene.


.0002 ANEMIA, SIDEROBLASTIC, 1

ALAS2, THR388SER
  
RCV000011215

In 2 affected males and 1 carrier female in a kindred with X-linked pyridoxine-responsive sideroblastic anemia-1 (SIDBA1; 300751), Cox et al. (1994) demonstrated a cytosine-to-guanine change at nucleotide 1215 in exon 8. This change resulted in the substitution of serine for threonine at amino acid residue 388, near the lysine that binds the pyridoxal phosphate cofactor. In expression studies, the activity of the mutant enzyme was reduced relative to that of the wildtype. Although the affinity of the mutant enzyme for pyridoxal phosphate was not altered, the mutation appeared to introduce a conformational change at the active site of the enzyme.

By crystal structure analysis of Alas2 from Rhodobacter capsulatus, Astner et al. (2005) determined that thr388 is part of the PLP recognition pattern. Substitution of threonine by serine would allow for higher rotational freedom of serine, significantly reducing the affinity of ALAS for PLP. Correspondingly, patients would respond favorably to pyridoxine treatment.


.0003 ANEMIA, SIDEROBLASTIC, 1

ALAS2, PHE165LEU
  
RCV000011216...

In the original family with X-linked sideroblastic anemia-1 (SIDBA1; 300751) described by Cooley (1945), Cotter et al. (1994) found that the ALAS2 gene harbored an A-to-C transversion in exon 5, predicted to result in the substitution of leucine for phenylalanine at residue 165 (F165L). The mutation occurred in the first highly conserved domain of the ALAS2 catalytic core shared by all species.

By crystal structure analysis of Alas2 from Rhodobacter capsulatus, Astner et al. (2005) determined that phe165 structurally stabilizes the neighboring arg163, required for sCoA carboxylate group recognition, through hydrophobic interactions. Replacing phe165 by leucine destabilizes arg163, reducing the specificity of sCoA binding. As PLP binding is not affected by the mutation, response to pyridoxine treatment was predicted to be marginal.


.0004 ANEMIA, SIDEROBLASTIC, 1

ALAS2, GLY291SER
  
RCV000011217

In a large kindred with a pyridoxine-sensitive form of X-linked sideroblastic anemia-1 (SIDBA1; 300751), Prades et al. (1995) found a G-to-A transition at nucleotide 871 of the coding sequence (exon 7) of the ALAS2 gene. This resulted in a gly291-to-ser amino acid substitution. The glycine is conserved through evolution in ALAS proteins deduced from DNA sequences of a large number of different organisms. With a PCR assay, they demonstrated the mutation in 3 affected males and 2 female carriers, whereas the carrier status was excluded in 8 females at risk. Early detection of the mutant allele in family members may be important for the prevention of anemia in males and of ion overload both in affected males and carrier females.

By crystal structure analysis of Alas2 from Rhodobacter capsulatus, Astner et al. (2005) determined that replacement of gly291 by ser would decrease the affinity of ALAS for sCoA. Furthermore, gly291 is 1 helical turn away from his285, which is involved in PLP binding. As a result, this mutation may be counteracted by increasing levels of PLP.


.0005 ANEMIA, SIDEROBLASTIC, 1, LATE-ONSET

ALAS2, LYS299GLN
  
RCV000011218

Cotter et al. (1995) reported 2 unrelated cases of X-linked sideroblastic anemia-1 (SIDBA1; 300751) that were atypical in 2 respects: unlike the usual form which is manifest in the first 3 decades of life and in which the hematologic response to pyridoxine is variable and rarely complete, the 2 patients were highly pyridoxine-responsive and were in the geriatric age group. A previously unaffected 77-year-old male and an 81-year-old female, who were previously well, were found to have developed severe hypochromic, microcytic anemia with ringed sideroblasts in the bone marrow, which responded dramatically to pyridoxine with normalization of hemoglobin values. Sequence analysis identified an A-to-C transversion in exon 7 (K299Q) of the ALAS2 gene in the man as well as his daughter, while the female proband showed a G-to-A transition in exon 5 (A172T; 301300.0006). The latter mutation resulted in decreased in vitro stability of bone marrow delta-aminolevulinate synthase activity. The recombinant mutant ALAS2 enzyme of each patient had marked thermal lability. Addition of pyridoxal 5-prime-phosphate in vitro stabilized the mutant enzymes, consistent with the observed dramatic response to pyridoxine in vivo. This late-onset form of X-linked sideroblastic anemia could be distinguished from refractory anemia and ringed sideroblasts by microcytosis, pyridoxine-responsiveness, and, of course, ALAS2 mutations. Cotter et al. (1995) suggested that all patients with acquired sideroblastic anemia should be tested for pyridoxine responsiveness. Relatively modest deficiencies of folate or vitamin B12 may explain late-onset anemia in patients with previously compensated hemolytic states due to inherited cytoskeletal defects, e.g., hereditary spherocytosis, or glycolytic pathway enzyme deficiencies, e.g., pyruvate kinase deficiency. The authors stated that age-associated nutritional deficiencies due to subtle alterations in vitamin B6 availability or metabolism may unmask an inherited disorder when a mutation is present in a gene that encodes a protein highly dependent upon the normal availability of pyridoxal phosphate.

By crystal structure analysis of Alas2 from Rhodobacter capsulatus, Astner et al. (2005) determined that replacement of lys299 by glutamine causes decreased binding affinity of ALAS for sCoA. Patients with this mutation have been reported to respond to pyridoxine treatment; however, as PLP binding in ALAS is not affected by the mutation, the effect of pyridoxine supplementation may be indirect.


.0006 ANEMIA, SIDEROBLASTIC, 1, LATE-ONSET

ALAS2, ALA172THR
  
RCV000011219...

.0007 ANEMIA, SIDEROBLASTIC, 1, PYRIDOXINE REFRACTORY

ALAS2, ASP190VAL
  
RCV003322588

In a patient with X-linked sideroblastic anemia-1 (SIDBA1; 300751), Furuyama et al. (1997) identified a 621A-T transversion in the ALAS2 gene that led to an asp190-to-val amino acid substitution. The anemia was refractory to pyridoxine treatment.


.0008 ANEMIA, SIDEROBLASTIC, 1

ALAS2, ARG411CYS
  
RCV000011221...

In a Japanese patient with pyridoxine-responsive X-linked sideroblastic anemia-1 (SIDBA1; 300751), Furuyama et al. (1998) identified an arg411-to-cys missense mutation of the ALAS2 gene. The normal and mutant cDNAs were expressed in E. coli, and mutant enzyme protein was found to have 12% and 25% ALAS activity when incubated in the absence and presence of pyridoxal 5-prime-phosphate, respectively, compared with that of the wildtype enzyme.


.0009 ANEMIA, SIDEROBLASTIC, 1

ALAS2, SER568GLY
  
RCV000011222

In an 18-year-old Japanese male with sideroblastic anemia-1 (SIDBA1; 300751), Harigae et al. (1999) identified a 1754A-G missense mutation in exon 11 of the ALAS2 gene, resulting in a ser568-to-gly amino acid substitution. ALAS activity in bone marrow cells of the patient was reduced to 53.3% of the normal control. Consistent with this finding, activity of a bacterially expressed ALAS2 mutant protein harboring this mutation was 19.5% compared with the normal control, but was increased up to 31.6% by the addition of pyridoxal 5-prime-phosphate in vitro. RFLP analysis with BspHI restriction revealed that the mother was a carrier of the mutation. Harigae et al. (1999) stated that 23 different mutations encompassing exons of the catalytic region of the ALAS2 gene had been described. The 1754A-G mutation was the only one located in exon 11.


.0010 ANEMIA, SIDEROBLASTIC, 1

ALAS2, CYS395TYR
  
RCV000011223

Cazzola et al. (2000) identified a missense mutation in the ALAS2 gene in a 72-year-old woman whose hemoglobin level had been normal at the age of 36 years. She later presented at age 64 with breathlessness and fatigue and was found to have severe microcytic anemia. Because of microcytosis and pyridoxine responsiveness, the patient was thought to have late-onset X-linked sideroblastic anemia-1 (SIDBA1; 300751). She was found to be heterozygous for a G-to-A transition at nucleotide 1236 in exon 9, which resulted in a cys395-to-tyr amino acid substitution. She expressed only the mutated gene in reticulocytes. Her 2 daughters and a granddaughter were heterozygous for this mutation but had normal hemoglobin levels and expressed the normal ALAS2 gene in reticulocytes. A grandson with a previous diagnosis of thalassemia intermedia was found to be hemizygous for the same ALAS2 mutation. Treatment with pyridoxine completely corrected the anemia in the grandson as well as in the proband.

By crystal structure analysis of Alas2 from Rhodobacter capsulatus, Astner et al. (2005) determined that replacement of cys395 by the significantly larger tyrosine would adversely affect PLP binding. Correspondingly, the activity of this mutant enzyme could be rescued by higher concentrations of PLP.


.0011 ANEMIA, SIDEROBLASTIC, 1

ALAS2, ASP159TYR
  
RCV000011224

In 2 affected males from a family with pyridoxine-responsive X-linked sideroblastic anemia (SIDBA1; 300751), Hurford et al. (2002) identified an asp159-to-tyr (D159Y) mutation in the ALAS2 gene. Another mutation at codon 159 has also been reported (D159N; 301300.0012).


.0012 ANEMIA, SIDEROBLASTIC, 1

ALAS2, ASP159ASN
  
RCV000011225

In an 81-year-old man in whom X-linked sideroblastic anemia-1 (SIDBA1; 300751) was precipitated by maintenance hemodialysis therapy, Furuyama et al. (2003) identified heterozygosity for a 527G-A transition in exon 5 of the ALAS2 gene, resulting in an asp159-to-asn (D159N) mutation. Other members of the family could not be studied. The D159N mutation did not appear to be a polymorphism, as it was not found in 44 ALAS2 control alleles from the Japanese population.


.0013 ANEMIA, SIDEROBLASTIC, 1

ALAS2, -206C-G, PROMOTER
  
RCV000011226...

In a 32-year-old woman with sideroblastic anemia-1 (SIDBA1; 300751) of mild phenotype and moderately late onset, Bekri et al. (2003) found a promoter mutation in the ALAS2 gene, a C-to-G transversion at nucleotide -206 from the transcription start site, as defined by primer extension. The same mutation was found in her affected son but not in any of her unaffected relatives. Pyridoxine therapy had no effect in the proband, but in her affected son engendered a modest increase in hemoglobin concentration and a 4-fold reduction in ferritin iron.


.0014 ANEMIA, SIDEROBLASTIC, 1

ALAS2, HIS524ASP
  
RCV000011227

In a male with hereditary sideroblastic anemia-1 (SIDBA1; 300751), Edgar and Wickramasinghe (1998) identified a 1622C-G transversion in exon 10 of the ALAS2 gene, resulting in a his524-to-asp (H524D) substitution. This histidine is highly conserved. The proband's mother and sister were heterozygous carriers of the mutation.


.0015 PROTOPORPHYRIA, ERYTHROPOIETIC, X-LINKED DOMINANT

ALAS2, 4-BP DEL, 1706AGTG
  
RCV000011228...

In 6 families with X-linked erythropoietic protoporphyria (XLEPP; 300752), Whatley et al. (2008) identified a 4-bp deletion in exon 11 of the ALAS2 gene (1706_1709delAGTG). The mutation occurred on 5 different haplotypes, suggesting that it had arisen on at least 5 separate occasions. Expression studies in E. coli showed that this deletion resulted in a marked increase in ALAS2 activity and that some of the 5-aminolevulinate (ALA) that is produced is further metabolized to porphyrin. These findings of a gain of function strongly suggested that protoporphyrin and its zinc chelate accumulate in XLEPP because the rate of ALA formation is increased to such an extent that insertion of iron into protoporphyrin by ferrochelatase (FECH; 612386) becomes rate limiting for heme synthesis.

Ducamp et al. (2013) identified the c.1706delAGTG mutation in 2 unrelated girls, of Swiss and French origin, respectively, with XLEPP. Both had severe photosensitivity by 3 years of age, iron deficiency, and increased erythrocyte zinc-protoporphyrin. One patient had gallstones. The mother of the French girl had a milder form of the disorder and was found to be germline and somatic mosaic for the mutation. In vitro functional expression assays in E. coli showed that the mutant enzyme had increased ALAS2 catalytic activity consistent with a gain of function. There was no evidence of a founder effect, suggesting that the mutation may represent a hotspot.


.0016 PROTOPORPHYRIA, ERYTHROPOIETIC, X-LINKED DOMINANT

ALAS2, 2-BP DEL, 1699AT
  
RCV000011229

In 2 families from southwest England with X-linked erythropoietic protoporphyria (XLEPP; 300752), Whatley et al. (2008) identified a 2-bp deletion in exon 11 of ALAS2 (1699_1700delAT). This deletion occurred on the same haplotype in both families. This mutation when expressed in E. coli resulted in a gain of function of ALAS2 activity.


.0017 ANEMIA, SIDEROBLASTIC, 1

ALAS2, TYR199HIS
  
RCV000011230

In a male proband with pyridoxine-responsive hereditary sideroblastic anemia-1 (SIDBA1; 300751), Cotter et al. (1999) identified a 647T-C transition in exon 5 of the ALAS2 gene, resulting in a tyr199-to-his (Y199H) substitution. The mother was heterozygous for the mutation, which was not found in any other family member or in any of 100 normal alleles. The proband had severe and early iron loading coinherited hereditary hemochromatosis with a homozygous C232Y mutation in the HFE gene (235200.0001). Reversal of the iron overload in this patient resulted in higher hemoglobin concentrations during pyridoxine supplementation.


.0018 ANEMIA, SIDEROBLASTIC, 1

ALAS2, ARG452CYS
  
RCV000011231...

In a male proband with pyridoxine-responsive hereditary sideroblastic anemia-1 (SIDBA1; 300751), Cotter et al. (1999) identified a 1406C-T transition in exon 9 of the ALAS2 gene, resulting in an arg452-to-cys (R452C) substitution. The mutation was not found in any of 100 normal alleles. Cotter et al. (1999) stated that the same mutation had been found in another family with XLSA.


.0019 PROTOPORPHYRIA, ERYTHROPOIETIC, X-LINKED DOMINANT

ALAS2, GLN548TER
  
RCV000054488

In an Australian girl with X-linked erythropoietic protoporphyria (300752), Ducamp et al. (2013) identified a heterozygous c.1642C-T transition in exon 11 of the ALAS2 gene, resulting in a gln548-to-ter (Q548X) substitution. The mutation was not found in 100 control chromosomes or a large control database. The patient had onset in childhood of severe photosensitivity associated with increased liver enzymes, iron deficiency, and increased erythrocyte zinc-protoporphyrin. In vitro functional expression assays in E. coli showed that the mutant enzyme had increased ALAS2 catalytic activity, consistent with a gain of function.


.0020 PROTOPORPHYRIA, ERYTHROPOIETIC, X-LINKED DOMINANT

ALAS2, 26-BP DEL, NT1651
  
RCV000054489

In a Dutch girl, whose parents originally came from Afghanistan, with XLDPP (300752), Ducamp et al. (2013) identified a heterozygous 26-bp deletion (c.1651_1677) in exon 11 of the ALAS2 gene, resulting in a frameshift and premature termination (Ser551ProfsTer5). The mutation was not found in 100 control chromosomes or in a large control database. The patient had onset in infancy of severe photosensitivity associated with elevated liver enzymes and increased erythrocyte zinc-protoporphyrin. In vitro functional expression assays in E. coli showed that the mutant enzyme had increased ALAS2 catalytic activity, consistent with a gain of function.


REFERENCES

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  16. Cotter, P. D., May, A., Li, L., Al-Sabah, A. I., Fitzsimons, E. J., Cazzola, M., Bishop, D. F. Four new mutations in the erythroid-specific 5-aminolevulinate synthase (ALAS2) gene causing X-linked sideroblastic anemia: increased pyridoxine responsiveness after removal of iron overload by phlebotomy and coinheritance of hereditary hemochromatosis. Blood 93: 1757-1769, 1999. [PubMed: 10029606, related citations]

  17. Cotter, P. D., Rucknagel, D. L., Bishop, D. F. X-linked sideroblastic anemia: identification of the mutation in the erythroid-specific delta-aminolevulinate synthase gene (ALAS2) in the original family described by Cooley. Blood 84: 3915-3924, 1994. [PubMed: 7949148, related citations]

  18. Cotter, P. D., Willard, H. F., Gorski, J. L., Bishop, D. F. Assignment of human erythroid delta-aminolevulinate synthase (ALAS2) to a distal subregion of band Xp11.21 by PCR analysis of somatic cell hybrids containing X;autosome translocations. Genomics 13: 211-212, 1992. [PubMed: 1577484, related citations] [Full Text]

  19. Cox, T. C., Bawden, M. J., Abraham, N. G., Bottomley, S. S., May, B. K., Baker, E., Chen, L. Z., Sutherland, G. R. Erythroid 5-aminolevulinate synthase is located on the X chromosome. Am. J. Hum. Genet. 46: 107-111, 1990. [PubMed: 2294742, related citations]

  20. Cox, T. C., Bottomley, S. S., Wiley, J. S., Bawden, M. J., Matthews, C. S., May, B. K. X-linked pyridoxine-responsive sideroblastic anemia due to a thr388-to-ser substitution in erythroid 5-aminolevulinate synthase. New Eng. J. Med. 330: 675-679, 1994. [PubMed: 8107717, related citations] [Full Text]

  21. Cox, T. C., Kozman, H. M., Raskind, W. H., May, B. K., Mulley, J. C. Identification of a highly polymorphic marker within intron 7 of the ALAS2 gene and suggestion of at least two loci for X-linked sideroblastic anemia. Hum. Molec. Genet. 1: 639-641, 1992. [PubMed: 1301172, related citations] [Full Text]

  22. Ducamp, S., Schneider-Yin, X., de Rooij, F., Clayton, J., Fratz, E. J., Rudd, A., Ostapowicz, G., Varigos, G., Lefebvre, T., Deybach, J.-C., Gouya, L., Wilson, P., Ferreira, G. C., Minder, E. I., Puy, H. Molecular and functional analysis of the C-terminal region of human erythroid-specific 5-aminolevulinic synthase associated with X-linked dominant protoporphyria (XLDPP). Hum. Molec. Genet. 22: 1280-1288, 2013. [PubMed: 23263862, related citations] [Full Text]

  23. Edgar, A. J., Wickramasinghe, S. N. Hereditary sideroblastic anaemia due to a mutation in exon 10 of the erythroid 5-aminolaevulinate synthase gene. Brit. J. Haemat. 100: 389-392, 1998. [PubMed: 9488633, related citations] [Full Text]

  24. Elves, M. W., Bourne, M. S., Israels, M. C. G. Pyridoxine-responsive anaemia determined by an X-linked gene. J. Med. Genet. 3: 1-4, 1966. [PubMed: 5911826, related citations] [Full Text]

  25. Furuyama, K., Fujita, H., Nagai, T., Yomogida, K., Munakata, H., Kondo, M., Kimura, A., Kuramoto, A., Hayashi, N., Yamamoto, M. Pyridoxine refractory X-linked sideroblastic anemia caused by a point mutation in the erythroid 5-aminolevulinate synthase gene. Blood 90: 822-830, 1997. [PubMed: 9226183, related citations]

  26. Furuyama, K., Harigae, H., Kinoshita, C., Shimada, T., Miyaoka, K., Kanda, C., Maruyama, Y., Shibahara, S., Sassa, S. Late-onset X-linked sideroblastic anemia following hemodialysis. Blood 101: 4623-4624, 2003. [PubMed: 12531813, related citations] [Full Text]

  27. Furuyama, K., Uno, R., Urabe, A., Hayashi, N., Fujita, H., Kondo, M., Sassa, S., Yamamoto, M. R411C mutation of the ALAS2 gene encodes a pyridoxine-responsive enzyme with low activity. Brit. J. Haemat. 103: 839-841, 1998. [PubMed: 9858242, related citations] [Full Text]

  28. Han, L., Lu, J., Pan, L., Wang, X., Shao, Y., Han, S., Huang, B. Histone acetyltransferase p300 regulates the transcription of human erythroid-specific 5-aminolevulinate synthase gene. Biochem. Biophys. Res. Commun. 348: 799-806, 2006. [PubMed: 16904069, related citations] [Full Text]

  29. Harigae, H., Furuyama, K., Kimura, A., Neriishi, K., Tahara, N., Kondo, M., Hayashi, N., Yamamoto, M., Sassa, S., Sasaki, T. A novel mutation of the erythroid-specific delta-aminolaevulinate synthase gene in a patient with X-linked sideroblastic anaemia. Brit. J. Haemat. 106: 175-177, 1999. [PubMed: 10444183, related citations] [Full Text]

  30. Hurford, M. T., Marshall-Taylor, C., Vicki, S. L., Zhou, J. Z., Silverman, L. M., Rezuke, W. N., Altman, A., Tsongalis, G. J. A novel mutation in exon 5 of the ALAS2 gene results in X-linked sideroblastic anemia. Clin. Chim. Acta 321: 49-53, 2002. [PubMed: 12031592, related citations] [Full Text]

  31. Prades, E., Chambon, C., Dailey, T. A., Dailey, H. A., Briere, J., Grandchamp, B. A new mutation of the ALAS2 gene in a large family with X-linked sideroblastic anemia. Hum. Genet. 95: 424-428, 1995. [PubMed: 7705839, related citations] [Full Text]

  32. Puck, J. M., Willard, H. F. X inactivation in females with X-linked disease. New Eng. J. Med. 338: 325-327, 1998. [PubMed: 9445416, related citations] [Full Text]

  33. Raskind, W. H., Wijsman, E., Pagon, R. A., Cox, T. C., Bawden, M. J., May, B. K., Bird, T. D. X-linked sideroblastic anemia and ataxia: linkage to phosphoglycerate kinase at Xq13. Am. J. Hum. Genet. 48: 335-341, 1991. [PubMed: 1671320, related citations]

  34. Surinya, K. H., Cox, T. C., May, B. K. Identification and characterization of a conserved erythroid-specific enhancer located in intron 8 of the human 5-aminolevulinate synthase 2 gene. J. Biol. Chem. 273: 16798-16809, 1998. [PubMed: 9642238, related citations] [Full Text]

  35. Whatley, S. D., Ducamp, S., Gouya, L., Grandchamp, B., Beaumont, C., Badminton, M. N., Elder, G. H., Holme, S. A., Anstey, A. V., Parker, M., Corrigall, A. V., Meissner, P. N., Hift, R. J., Marsden, J. T., Ma, Y., Mieli-Vergani, G., Deybach, J.-C., Puy, H. C-terminal deletions in the ALAS2 gene lead to gain of function and cause X-linked dominant protoporphyria without anemia or iron overload. Am. J. Hum. Genet. 83: 408-414, 2008. [PubMed: 18760763, images, related citations] [Full Text]


Cassandra L. Kniffin - updated : 8/8/2013
Patricia A. Hartz - updated : 4/8/2009
Cassandra L. Kniffin - updated : 12/3/2008
Ada Hamosh - updated : 11/5/2008
Carol A. Bocchini - updated : 11/4/2008
George E. Tiller - updated : 10/15/2003
Victor A. McKusick - updated : 9/15/2003
Victor A. McKusick - updated : 2/14/2001
Victor A. McKusick - updated : 9/15/2000
Victor A. McKusick - updated : 10/5/1999
Victor A. McKusick - updated : 4/16/1999
Victor A. McKusick - updated : 2/2/1999
Victor A. McKusick - updated : 10/23/1998
Victor A. McKusick - updated : 6/25/1998
Victor A. McKusick - updated : 6/18/1998
Victor A. McKusick - updated : 10/29/1997
Creation Date:
Victor A. McKusick : 6/4/1986
alopez : 12/11/2017
carol : 03/17/2016
carol : 3/16/2016
ckniffin : 3/16/2016
carol : 8/14/2013
ckniffin : 8/8/2013
mgross : 4/9/2009
terry : 4/8/2009
carol : 12/3/2008
ckniffin : 12/3/2008
alopez : 12/2/2008
alopez : 12/2/2008
terry : 11/5/2008
carol : 11/4/2008
carol : 3/17/2004
cwells : 10/15/2003
tkritzer : 9/23/2003
tkritzer : 9/17/2003
tkritzer : 9/15/2003
carol : 11/24/2001
cwells : 2/19/2001
terry : 2/14/2001
terry : 9/15/2000
carol : 10/13/1999
terry : 10/5/1999
carol : 4/19/1999
terry : 4/16/1999
carol : 4/2/1999
carol : 2/15/1999
terry : 2/2/1999
carol : 10/23/1998
alopez : 6/26/1998
terry : 6/25/1998
carol : 6/19/1998
terry : 6/18/1998
mark : 11/3/1997
terry : 10/29/1997
carol : 6/20/1997
mark : 1/25/1996
terry : 1/22/1996
terry : 10/27/1995
mark : 8/25/1995
carol : 2/17/1995
mimadm : 2/27/1994
carol : 11/30/1992
carol : 6/3/1992

* 301300

DELTA-AMINOLEVULINATE SYNTHASE 2; ALAS2


Alternative titles; symbols

ALAS, ERYTHROID; ALASE
5-AMINOLEVULINATE SYNTHASE, ERYTHROID-SPECIFIC


HGNC Approved Gene Symbol: ALAS2

SNOMEDCT: 1197360001, 48983004;   ICD10CM: D64.0;  


Cytogenetic location: Xp11.21     Genomic coordinates (GRCh38): X:55,009,055-55,030,977 (from NCBI)


Gene-Phenotype Relationships

Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
Xp11.21 Anemia, sideroblastic, 1 300751 X-linked recessive 3
Protoporphyria, erythropoietic, X-linked 300752 X-linked 3

TEXT

Description

Delta-aminolevulinate synthase (ALAS; EC 2.3.1.27) catalyzes the first committed step of heme biosynthesis, which is the synthesis of 5-aminolevulinic acid, the first common precursor of all tetrapyrroles, from glycine and succinyl-coenzyme A (sCoA) in a pyridoxal 5-phosphate (PLP)-dependent manner (Astner et al., 2005). Two forms of ALAS exist in humans: a housekeeping form encoded by the ALAS1 gene (125290), and an erythroid tissue-specific form encoded by the ALAS2 gene (Bishop et al., 1990).


Cloning and Expression

Astrin and Bishop (1989) isolated the ALAS2 gene from an erythroid human fetal liver library. ALAS2 appeared to be expressed only in erythroid cells.


Gene Structure

Surinya et al. (1998) determined that the ALAS2 gene spans about 35 kb and contains 11 exons. An erythroid-specific enhancer in intron 8 contains GATA and CACCC boxes that are conserved in mouse and canine Alas2.


Mapping

Benoff and Skoultchi (1977) presented 3 lines of evidence that a locus on the X chromosome in the mouse controls hemoglobin synthesis. Following Ohno's law, one would expect the same locus to exist in man.

Benoff et al. (1978) identified in the mouse an X-linked locus that inhibits hemoglobin production by inhibiting inducible heme biosynthesis, probably at the step catalyzed by delta-aminolevulinic acid synthetase. Close linkage to the Xg locus was excluded by Elves et al. (1966).

Astrin et al. (1987) mapped the ALAS1 gene to chromosome 3, excluding it as a candidate gene for X-linked hypochromic anemia. Later, however, Astrin and Bishop (1989) isolated a second ALAS gene, ALAS2, and by Southern blot analysis of DNAs from somatic cell hybrids, assigned it to the X chromosome. Also see Bishop et al. (1990).

By Southern analysis of a mouse/human hybrid cell panel and by in situ hybridization, Cox et al. (1990) mapped the ALAS2 gene to chromosome Xp21-q21, with the most likely location being on band Xp11.2.

By analysis of DNA from hybrid clones containing translocations in the region Xp11.21-q21.3, Cotter et al. (1992) achieved finer localization of the ALAS2 gene with respect to other loci and breakpoints within this region. They localized the ALAS2 gene to subregion Xp11.21. Cox et al. (1992) identified a highly polymorphic marker, a compound dinucleotide repeat, within intron 7 of the ALAS2 gene and used it to confirm the localization of ALAS2 in the multipoint linkage map of the X chromosome. No recombination was observed between ALAS2 and the centromere marker DXZ1. No recombination was found with DXS14. Since Raskind et al. (1991) excluded linkage of DXS14 and X-linked sideroblastic anemia with spinocerebellar ataxia within 5 to 10 cM, one can probably conclude that there are at least 2 loci on the X chromosome determining sideroblastic anemia. One locus may be located on the proximal portion of Xq.

In the course of high-resolution comparative mapping of the proximal region of the mouse X chromosome, Blair et al. (1995) demonstrated the location of the Alas2 gene relative to others.


Gene Function

Using a reporter gene assay, Surinya et al. (1998) showed that intron 8 of the ALAS2 gene harbored strong orientation-dependent erythroid-specific enhancer activity. In vitro assays showed that GATA1 (305371) and SP1 (189906) bound the GATA and CACCC boxes within this region, respectively.

Han et al. (2006) showed that histone deacetylase (HDAC; see 601241) inhibitors increased ALAS2 expression in a human erythroid cell line. Increased ALAS2 expression was concurrent with increased acetylation of histone H4 (see 602822) at the ALAS2 promoter. Histone acetyltransferase p300 (EP300; 602700) bound the ALAS2 promoter, and overexpression of p300 increased promoter reporter expression and endogenous ALAS2 mRNA levels. The GATA1 and SP1 sites at the ALAS2 promoter synergistically contributed to p300-mediated ALAS2 activation.


Biochemical Features

Astner et al. (2005) determined the crystal structure of homodimeric Alas from Rhodobacter capsulatus, which shares 49% sequence identity with human ALAS. Mutations in the ALAS gene resulting in X-linked sideroblastic anemia were predicted to obstruct substrate binding, disrupt the dimer interface, or hamper proper folding (see, e.g., 301300.0002-301300.0005). The findings provided explanations for potential responsiveness to pyridoxine treatment in some cases.


Molecular Genetics

Sideroblastic Anemia 1, X-Linked

Aoki et al. (1973) found deficiency of delta-aminolevulinic acid synthetase in the red cells of patients with sideroblastic anemia-1 (SIDBA1; 300751), some of whom were males with congenital anemia which in some responded to treatment with vitamin B6.

In a 30-year-old Chinese male with a pyridoxine-responsive form of X-linked sideroblastic anemia, Cotter et al. (1992) identified a mutation in the ALAS2 gene (301300.0001).

Cotter et al. (1995) described a previously unaffected 81-year-old woman in whom microcytic sideroblastic anemia developed. She was found to be heterozygous for a point mutation of the ALAS2 gene (301300.0005). The initial diagnosis was myelodysplastic syndrome, but the recognition of the X-linked congenital sideroblastic anemia allowed successful treatment with pyridoxine. There is evidence from other sources that skewed lyonization can be an acquired pattern. In the study of peripheral blood leukocytes by Busque et al. (1996), the incidence of skewing was 1.9% in neonates, 4.5% in women who were 28 to 32 years old, and 22.7% in women who were 60 years of age or older. Cazzola and Bergamaschi (1998) estimated that in 30 to 40% of elderly women, hematopoietic cells (erythroid cells, granulocytic cells, monocytes, and megakaryocytes) have more than 90% expression of 1 parental X chromosome. Puck and Willard (1998) reviewed mechanisms for a skewed pattern with a diagram of 3 different mechanisms.

In each of 4 unrelated males with X-linked sideroblastic anemia, Cotter et al. (1999) identified new mutations: 647T-C, 1283C-T, 1395G-A, and 1406C-T predicting amino acid substitutions tyr199 to his (Y199H; 301300.0017), arg411 to cys (R411C; 301300.0008), arg448 to gln (R448Q), and arg452 to cys (R452C; 301300.0018), respectively. All probands were clinically pyridoxine-responsive. The Y199H mutation was demonstrated to be the first de novo XLSA mutation, having occurred in a gamete of the proband's maternal grandfather. In 18 unrelated XLSA hemizygotes, Cotter et al. (1999) found a significantly higher frequency of coinheritance of the hereditary hemochromatosis HFE mutant allele C282Y (235200.0001) than found in the normal population. One proband with the Y199H mutation with severe and early iron loading was homozygous for C282Y.

In an 81-year-old man who developed sideroblastic anemia while undergoing hemodialysis, Furuyama et al. (2003) identified heterozygosity for an asp159-to-asn change in the ALAS2 gene (D159N; 301300.0012).

Erythropoietic Protoporphyria, X-Linked

In 8 families with X-linked dominant erythropoietic protoporphyria (XLEPP; 300752), Whatley et al. (2008) identified 2 deletion mutations in exon 11 of the ALAS2 gene (301300.0015 and 301300.0016). The mutations were not found in 129 unrelated patients with other forms of erythropoietic protoporphyria or 100 normal chromosomes. The data of Whatley et al. (2008) demonstrated that disruption of the C-terminal region of ALAS2 leads to the production of protoporphyrin in excess of the amount required for hemoglobinization and in quantities sufficient to cause photosensitivity and liver damage, in spite of normal ferrochelatase (FECH; 612386) activity.

In 4 unrelated girls with X-linked dominant erythropoietic protoporphyria, Ducamp et al. (2013) identified 3 different heterozygous mutations in the ALAS2 gene. One was recurrent (delAGTG; 301300.0015) and the other 2 were novel (301300.0019 and 301300.0020). All occurred in the last exon of the ALAS2 gene, and all were shown in vitro to result in increased ALAS2 catalytic activity, consistent with a gain of function. All 4 girls presented in early childhood with severe photosensitivity associated with increased erythrocyte zinc- and metal-free protoporphyrin. Two had elevated liver enzymes, 1 had gallstones, and most had iron deficiency. The mother of 1 child was mildly affected and was shown to be somatic and germline mosaic for the mutation. By generating a series of ALAS2 variants, Ducamp et al. (2013) found that the 'gain-of-function domain' contains a minimum of 33 amino acids between residues 544 and 576 in the C terminus of the protein.


ALLELIC VARIANTS 20 Selected Examples):

.0001   ANEMIA, SIDEROBLASTIC, 1

ALAS2, ILE471ASN
SNP: rs137852299, ClinVar: RCV000011214

In a 30-year-old Chinese male with a pyridoxine-responsive form of X-linked sideroblastic anemia-1 (SIDBA1; 300751), Cotter et al. (1992) identified a T-to-A transition in codon 471 in a highly conserved region of exon 9 of the ALAS gene, resulting in an ile-to-asn substitution. The mutation interrupted contiguous hydrophobic residues and was predicted to transform a region of beta-sheet structure to a random-coil structure. Prokaryotic expression of the normal and mutant cDNAs showed that the mutant construct expressed low levels of enzymatic activity that required higher concentrations of pyridoxal 5-prime-phosphate to achieve maximal activation than did the normal enzyme. The amino acid substitution occurred in the exon containing the putative pyridoxal 5-prime-phosphate binding site. To identify the mutation, Cotter et al. (1992) amplified and sequenced the 11 exonic coding regions of the ALAS gene.


.0002   ANEMIA, SIDEROBLASTIC, 1

ALAS2, THR388SER
SNP: rs137852300, ClinVar: RCV000011215

In 2 affected males and 1 carrier female in a kindred with X-linked pyridoxine-responsive sideroblastic anemia-1 (SIDBA1; 300751), Cox et al. (1994) demonstrated a cytosine-to-guanine change at nucleotide 1215 in exon 8. This change resulted in the substitution of serine for threonine at amino acid residue 388, near the lysine that binds the pyridoxal phosphate cofactor. In expression studies, the activity of the mutant enzyme was reduced relative to that of the wildtype. Although the affinity of the mutant enzyme for pyridoxal phosphate was not altered, the mutation appeared to introduce a conformational change at the active site of the enzyme.

By crystal structure analysis of Alas2 from Rhodobacter capsulatus, Astner et al. (2005) determined that thr388 is part of the PLP recognition pattern. Substitution of threonine by serine would allow for higher rotational freedom of serine, significantly reducing the affinity of ALAS for PLP. Correspondingly, patients would respond favorably to pyridoxine treatment.


.0003   ANEMIA, SIDEROBLASTIC, 1

ALAS2, PHE165LEU
SNP: rs137852301, ClinVar: RCV000011216, RCV001857329

In the original family with X-linked sideroblastic anemia-1 (SIDBA1; 300751) described by Cooley (1945), Cotter et al. (1994) found that the ALAS2 gene harbored an A-to-C transversion in exon 5, predicted to result in the substitution of leucine for phenylalanine at residue 165 (F165L). The mutation occurred in the first highly conserved domain of the ALAS2 catalytic core shared by all species.

By crystal structure analysis of Alas2 from Rhodobacter capsulatus, Astner et al. (2005) determined that phe165 structurally stabilizes the neighboring arg163, required for sCoA carboxylate group recognition, through hydrophobic interactions. Replacing phe165 by leucine destabilizes arg163, reducing the specificity of sCoA binding. As PLP binding is not affected by the mutation, response to pyridoxine treatment was predicted to be marginal.


.0004   ANEMIA, SIDEROBLASTIC, 1

ALAS2, GLY291SER
SNP: rs137852302, ClinVar: RCV000011217

In a large kindred with a pyridoxine-sensitive form of X-linked sideroblastic anemia-1 (SIDBA1; 300751), Prades et al. (1995) found a G-to-A transition at nucleotide 871 of the coding sequence (exon 7) of the ALAS2 gene. This resulted in a gly291-to-ser amino acid substitution. The glycine is conserved through evolution in ALAS proteins deduced from DNA sequences of a large number of different organisms. With a PCR assay, they demonstrated the mutation in 3 affected males and 2 female carriers, whereas the carrier status was excluded in 8 females at risk. Early detection of the mutant allele in family members may be important for the prevention of anemia in males and of ion overload both in affected males and carrier females.

By crystal structure analysis of Alas2 from Rhodobacter capsulatus, Astner et al. (2005) determined that replacement of gly291 by ser would decrease the affinity of ALAS for sCoA. Furthermore, gly291 is 1 helical turn away from his285, which is involved in PLP binding. As a result, this mutation may be counteracted by increasing levels of PLP.


.0005   ANEMIA, SIDEROBLASTIC, 1, LATE-ONSET

ALAS2, LYS299GLN
SNP: rs137852303, ClinVar: RCV000011218

Cotter et al. (1995) reported 2 unrelated cases of X-linked sideroblastic anemia-1 (SIDBA1; 300751) that were atypical in 2 respects: unlike the usual form which is manifest in the first 3 decades of life and in which the hematologic response to pyridoxine is variable and rarely complete, the 2 patients were highly pyridoxine-responsive and were in the geriatric age group. A previously unaffected 77-year-old male and an 81-year-old female, who were previously well, were found to have developed severe hypochromic, microcytic anemia with ringed sideroblasts in the bone marrow, which responded dramatically to pyridoxine with normalization of hemoglobin values. Sequence analysis identified an A-to-C transversion in exon 7 (K299Q) of the ALAS2 gene in the man as well as his daughter, while the female proband showed a G-to-A transition in exon 5 (A172T; 301300.0006). The latter mutation resulted in decreased in vitro stability of bone marrow delta-aminolevulinate synthase activity. The recombinant mutant ALAS2 enzyme of each patient had marked thermal lability. Addition of pyridoxal 5-prime-phosphate in vitro stabilized the mutant enzymes, consistent with the observed dramatic response to pyridoxine in vivo. This late-onset form of X-linked sideroblastic anemia could be distinguished from refractory anemia and ringed sideroblasts by microcytosis, pyridoxine-responsiveness, and, of course, ALAS2 mutations. Cotter et al. (1995) suggested that all patients with acquired sideroblastic anemia should be tested for pyridoxine responsiveness. Relatively modest deficiencies of folate or vitamin B12 may explain late-onset anemia in patients with previously compensated hemolytic states due to inherited cytoskeletal defects, e.g., hereditary spherocytosis, or glycolytic pathway enzyme deficiencies, e.g., pyruvate kinase deficiency. The authors stated that age-associated nutritional deficiencies due to subtle alterations in vitamin B6 availability or metabolism may unmask an inherited disorder when a mutation is present in a gene that encodes a protein highly dependent upon the normal availability of pyridoxal phosphate.

By crystal structure analysis of Alas2 from Rhodobacter capsulatus, Astner et al. (2005) determined that replacement of lys299 by glutamine causes decreased binding affinity of ALAS for sCoA. Patients with this mutation have been reported to respond to pyridoxine treatment; however, as PLP binding in ALAS is not affected by the mutation, the effect of pyridoxine supplementation may be indirect.


.0006   ANEMIA, SIDEROBLASTIC, 1, LATE-ONSET

ALAS2, ALA172THR
SNP: rs137852304, gnomAD: rs137852304, ClinVar: RCV000011219, RCV001729346

See 301300.0005 and Cotter et al. (1995).


.0007   ANEMIA, SIDEROBLASTIC, 1, PYRIDOXINE REFRACTORY

ALAS2, ASP190VAL
SNP: rs28935484, ClinVar: RCV003322588

In a patient with X-linked sideroblastic anemia-1 (SIDBA1; 300751), Furuyama et al. (1997) identified a 621A-T transversion in the ALAS2 gene that led to an asp190-to-val amino acid substitution. The anemia was refractory to pyridoxine treatment.


.0008   ANEMIA, SIDEROBLASTIC, 1

ALAS2, ARG411CYS
SNP: rs137852305, ClinVar: RCV000011221, RCV003555997

In a Japanese patient with pyridoxine-responsive X-linked sideroblastic anemia-1 (SIDBA1; 300751), Furuyama et al. (1998) identified an arg411-to-cys missense mutation of the ALAS2 gene. The normal and mutant cDNAs were expressed in E. coli, and mutant enzyme protein was found to have 12% and 25% ALAS activity when incubated in the absence and presence of pyridoxal 5-prime-phosphate, respectively, compared with that of the wildtype enzyme.


.0009   ANEMIA, SIDEROBLASTIC, 1

ALAS2, SER568GLY
SNP: rs137852306, ClinVar: RCV000011222

In an 18-year-old Japanese male with sideroblastic anemia-1 (SIDBA1; 300751), Harigae et al. (1999) identified a 1754A-G missense mutation in exon 11 of the ALAS2 gene, resulting in a ser568-to-gly amino acid substitution. ALAS activity in bone marrow cells of the patient was reduced to 53.3% of the normal control. Consistent with this finding, activity of a bacterially expressed ALAS2 mutant protein harboring this mutation was 19.5% compared with the normal control, but was increased up to 31.6% by the addition of pyridoxal 5-prime-phosphate in vitro. RFLP analysis with BspHI restriction revealed that the mother was a carrier of the mutation. Harigae et al. (1999) stated that 23 different mutations encompassing exons of the catalytic region of the ALAS2 gene had been described. The 1754A-G mutation was the only one located in exon 11.


.0010   ANEMIA, SIDEROBLASTIC, 1

ALAS2, CYS395TYR
SNP: rs137852307, ClinVar: RCV000011223

Cazzola et al. (2000) identified a missense mutation in the ALAS2 gene in a 72-year-old woman whose hemoglobin level had been normal at the age of 36 years. She later presented at age 64 with breathlessness and fatigue and was found to have severe microcytic anemia. Because of microcytosis and pyridoxine responsiveness, the patient was thought to have late-onset X-linked sideroblastic anemia-1 (SIDBA1; 300751). She was found to be heterozygous for a G-to-A transition at nucleotide 1236 in exon 9, which resulted in a cys395-to-tyr amino acid substitution. She expressed only the mutated gene in reticulocytes. Her 2 daughters and a granddaughter were heterozygous for this mutation but had normal hemoglobin levels and expressed the normal ALAS2 gene in reticulocytes. A grandson with a previous diagnosis of thalassemia intermedia was found to be hemizygous for the same ALAS2 mutation. Treatment with pyridoxine completely corrected the anemia in the grandson as well as in the proband.

By crystal structure analysis of Alas2 from Rhodobacter capsulatus, Astner et al. (2005) determined that replacement of cys395 by the significantly larger tyrosine would adversely affect PLP binding. Correspondingly, the activity of this mutant enzyme could be rescued by higher concentrations of PLP.


.0011   ANEMIA, SIDEROBLASTIC, 1

ALAS2, ASP159TYR
SNP: rs137852308, ClinVar: RCV000011224

In 2 affected males from a family with pyridoxine-responsive X-linked sideroblastic anemia (SIDBA1; 300751), Hurford et al. (2002) identified an asp159-to-tyr (D159Y) mutation in the ALAS2 gene. Another mutation at codon 159 has also been reported (D159N; 301300.0012).


.0012   ANEMIA, SIDEROBLASTIC, 1

ALAS2, ASP159ASN
SNP: rs137852308, ClinVar: RCV000011225

In an 81-year-old man in whom X-linked sideroblastic anemia-1 (SIDBA1; 300751) was precipitated by maintenance hemodialysis therapy, Furuyama et al. (2003) identified heterozygosity for a 527G-A transition in exon 5 of the ALAS2 gene, resulting in an asp159-to-asn (D159N) mutation. Other members of the family could not be studied. The D159N mutation did not appear to be a polymorphism, as it was not found in 44 ALAS2 control alleles from the Japanese population.


.0013   ANEMIA, SIDEROBLASTIC, 1

ALAS2, -206C-G, PROMOTER
SNP: rs140772352, gnomAD: rs140772352, ClinVar: RCV000011226, RCV001520731

In a 32-year-old woman with sideroblastic anemia-1 (SIDBA1; 300751) of mild phenotype and moderately late onset, Bekri et al. (2003) found a promoter mutation in the ALAS2 gene, a C-to-G transversion at nucleotide -206 from the transcription start site, as defined by primer extension. The same mutation was found in her affected son but not in any of her unaffected relatives. Pyridoxine therapy had no effect in the proband, but in her affected son engendered a modest increase in hemoglobin concentration and a 4-fold reduction in ferritin iron.


.0014   ANEMIA, SIDEROBLASTIC, 1

ALAS2, HIS524ASP
SNP: rs137852309, ClinVar: RCV000011227

In a male with hereditary sideroblastic anemia-1 (SIDBA1; 300751), Edgar and Wickramasinghe (1998) identified a 1622C-G transversion in exon 10 of the ALAS2 gene, resulting in a his524-to-asp (H524D) substitution. This histidine is highly conserved. The proband's mother and sister were heterozygous carriers of the mutation.


.0015   PROTOPORPHYRIA, ERYTHROPOIETIC, X-LINKED DOMINANT

ALAS2, 4-BP DEL, 1706AGTG
SNP: rs387906472, ClinVar: RCV000011228, RCV001851788, RCV002287329

In 6 families with X-linked erythropoietic protoporphyria (XLEPP; 300752), Whatley et al. (2008) identified a 4-bp deletion in exon 11 of the ALAS2 gene (1706_1709delAGTG). The mutation occurred on 5 different haplotypes, suggesting that it had arisen on at least 5 separate occasions. Expression studies in E. coli showed that this deletion resulted in a marked increase in ALAS2 activity and that some of the 5-aminolevulinate (ALA) that is produced is further metabolized to porphyrin. These findings of a gain of function strongly suggested that protoporphyrin and its zinc chelate accumulate in XLEPP because the rate of ALA formation is increased to such an extent that insertion of iron into protoporphyrin by ferrochelatase (FECH; 612386) becomes rate limiting for heme synthesis.

Ducamp et al. (2013) identified the c.1706delAGTG mutation in 2 unrelated girls, of Swiss and French origin, respectively, with XLEPP. Both had severe photosensitivity by 3 years of age, iron deficiency, and increased erythrocyte zinc-protoporphyrin. One patient had gallstones. The mother of the French girl had a milder form of the disorder and was found to be germline and somatic mosaic for the mutation. In vitro functional expression assays in E. coli showed that the mutant enzyme had increased ALAS2 catalytic activity consistent with a gain of function. There was no evidence of a founder effect, suggesting that the mutation may represent a hotspot.


.0016   PROTOPORPHYRIA, ERYTHROPOIETIC, X-LINKED DOMINANT

ALAS2, 2-BP DEL, 1699AT
SNP: rs387906473, ClinVar: RCV000011229

In 2 families from southwest England with X-linked erythropoietic protoporphyria (XLEPP; 300752), Whatley et al. (2008) identified a 2-bp deletion in exon 11 of ALAS2 (1699_1700delAT). This deletion occurred on the same haplotype in both families. This mutation when expressed in E. coli resulted in a gain of function of ALAS2 activity.


.0017   ANEMIA, SIDEROBLASTIC, 1

ALAS2, TYR199HIS
SNP: rs137852310, ClinVar: RCV000011230

In a male proband with pyridoxine-responsive hereditary sideroblastic anemia-1 (SIDBA1; 300751), Cotter et al. (1999) identified a 647T-C transition in exon 5 of the ALAS2 gene, resulting in a tyr199-to-his (Y199H) substitution. The mother was heterozygous for the mutation, which was not found in any other family member or in any of 100 normal alleles. The proband had severe and early iron loading coinherited hereditary hemochromatosis with a homozygous C232Y mutation in the HFE gene (235200.0001). Reversal of the iron overload in this patient resulted in higher hemoglobin concentrations during pyridoxine supplementation.


.0018   ANEMIA, SIDEROBLASTIC, 1

ALAS2, ARG452CYS
SNP: rs137852311, gnomAD: rs137852311, ClinVar: RCV000011231, RCV000254885

In a male proband with pyridoxine-responsive hereditary sideroblastic anemia-1 (SIDBA1; 300751), Cotter et al. (1999) identified a 1406C-T transition in exon 9 of the ALAS2 gene, resulting in an arg452-to-cys (R452C) substitution. The mutation was not found in any of 100 normal alleles. Cotter et al. (1999) stated that the same mutation had been found in another family with XLSA.


.0019   PROTOPORPHYRIA, ERYTHROPOIETIC, X-LINKED DOMINANT

ALAS2, GLN548TER
SNP: rs397514730, ClinVar: RCV000054488

In an Australian girl with X-linked erythropoietic protoporphyria (300752), Ducamp et al. (2013) identified a heterozygous c.1642C-T transition in exon 11 of the ALAS2 gene, resulting in a gln548-to-ter (Q548X) substitution. The mutation was not found in 100 control chromosomes or a large control database. The patient had onset in childhood of severe photosensitivity associated with increased liver enzymes, iron deficiency, and increased erythrocyte zinc-protoporphyrin. In vitro functional expression assays in E. coli showed that the mutant enzyme had increased ALAS2 catalytic activity, consistent with a gain of function.


.0020   PROTOPORPHYRIA, ERYTHROPOIETIC, X-LINKED DOMINANT

ALAS2, 26-BP DEL, NT1651
SNP: rs879255567, ClinVar: RCV000054489

In a Dutch girl, whose parents originally came from Afghanistan, with XLDPP (300752), Ducamp et al. (2013) identified a heterozygous 26-bp deletion (c.1651_1677) in exon 11 of the ALAS2 gene, resulting in a frameshift and premature termination (Ser551ProfsTer5). The mutation was not found in 100 control chromosomes or in a large control database. The patient had onset in infancy of severe photosensitivity associated with elevated liver enzymes and increased erythrocyte zinc-protoporphyrin. In vitro functional expression assays in E. coli showed that the mutant enzyme had increased ALAS2 catalytic activity, consistent with a gain of function.


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Contributors:
Cassandra L. Kniffin - updated : 8/8/2013
Patricia A. Hartz - updated : 4/8/2009
Cassandra L. Kniffin - updated : 12/3/2008
Ada Hamosh - updated : 11/5/2008
Carol A. Bocchini - updated : 11/4/2008
George E. Tiller - updated : 10/15/2003
Victor A. McKusick - updated : 9/15/2003
Victor A. McKusick - updated : 2/14/2001
Victor A. McKusick - updated : 9/15/2000
Victor A. McKusick - updated : 10/5/1999
Victor A. McKusick - updated : 4/16/1999
Victor A. McKusick - updated : 2/2/1999
Victor A. McKusick - updated : 10/23/1998
Victor A. McKusick - updated : 6/25/1998
Victor A. McKusick - updated : 6/18/1998
Victor A. McKusick - updated : 10/29/1997

Creation Date:
Victor A. McKusick : 6/4/1986

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