Affinage

ALAS2

5-aminolevulinate synthase, erythroid-specific, mitochondrial · UniProt P22557

Length
587 aa
Mass
64.6 kDa
Annotated
2026-06-09
62 papers in source corpus 20 papers cited in narrative 20 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ALAS2 is the erythroid-specific mitochondrial enzyme that catalyzes the committed, rate-limiting condensation of glycine and succinyl-CoA in heme biosynthesis, and its activity is required to prevent cytoplasmic iron overload and oxidative stress in developing erythroblasts (PMID:12393610). Catalysis depends on pyridoxal 5'-phosphate (PLP), and numerous loss-of-function missense mutations (e.g. F165L, A172T, K299Q, R411C) reduce activity primarily by impairing PLP binding or enzyme stability/thermostability rather than abolishing the catalytic mechanism directly, explaining the pyridoxine responsiveness seen clinically in X-linked sideroblastic anemia (PMID:7949148, PMID:7560104, PMID:9858242, PMID:21309041, PMID:25705881). ALAS2 physically associates through its C-terminal residues with SUCLA2, the beta subunit of succinyl-CoA synthetase, coupling the enzyme to succinyl-CoA supply; certain XLSA mutations selectively disrupt this interaction while leaving intrinsic activity intact (PMID:10727444, PMID:22740690). The extreme C-terminus acts as an autoinhibitory element that constrains catalytic turnover and product release: gain-of-function C-terminal frameshift deletions and truncations increase Vmax and 5-aminolevulinate release at the cost of thermostability, causing protoporphyrin overproduction in X-linked protoporphyria (PMID:22740690, PMID:18760763, PMID:30678654, PMID:21653323). Enzyme output is further restrained by negative feedback in which heme binds ALAS2 as a reversible mixed inhibitor that locks the enzyme in an inactive conformation [PMID:bio_10.1101_2025.06.09.658730]. Erythroid-restricted expression is driven by a GATA1-bound enhancer in intron 1 that engages a long-range chromatin loop with an enhancer complex (GATA1, TAL1, LMO2, LDB1, Pol II) and the proximal promoter, and post-transcriptionally ALAS2 is repressed by miR-218 acting on its 3'-UTR (PMID:23935018, PMID:28123038, PMID:26703568).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 1994 High

    Established that XLSA-associated missense mutations reduce ALAS2 catalytic activity and that the defect can be partially corrected by its PLP cofactor, providing the biochemical basis for pyridoxine responsiveness.

    Evidence Prokaryotic expression and affinity purification of the F165L mutant with in vitro activity and PLP stabilization assays

    PMID:7949148

    Open questions at the time
    • Single mutation; did not address whether other XLSA residues act by the same mechanism
    • No structural model of the affected catalytic core
  2. 1995 High

    Extended the PLP-stabilization mechanism by showing distinct XLSA mutations confer thermolability that is rescued by cofactor, generalizing PLP-dependent destabilization as a disease mechanism.

    Evidence Recombinant expression of K299Q and A172T with thermostability and PLP stabilization assays; G290S characterized in heterologous expression

    PMID:7560104 PMID:7705839

    Open questions at the time
    • G290S characterization is minimal
    • Did not distinguish folding vs catalytic effects structurally
  3. 1998 Medium

    Quantified the residual activity and PLP dependence of an additional XLSA residue, reinforcing that cofactor availability governs mutant enzyme function.

    Evidence Prokaryotic expression and purification of R411C with activity assays ± PLP

    PMID:9858242

    Open questions at the time
    • Single mutation, single lab
    • No in vivo erythroid validation
  4. 2000 High

    Answered how ALAS2 is coupled to its substrate supply by identifying SUCLA2 as an isoform-specific physical partner, implicating complex formation in efficient succinyl-CoA utilization or mitochondrial import.

    Evidence Yeast two-hybrid screen of human bone marrow cDNA and co-immunoprecipitation; interaction disrupted by D190V

    PMID:10727444

    Open questions at the time
    • Functional consequence (succinyl-CoA channeling vs import) not directly demonstrated
    • Did not map the interaction interface
  5. 2002 High

    Defined the cellular phenotype of ALAS2 loss, showing its activity prevents cytoplasmic iron accumulation and oxidative stress without blocking erythroid maturation per se.

    Evidence Alas2-null ES cell erythroid differentiation with iron quantification, EM localization, and lipid peroxidation

    PMID:12393610

    Open questions at the time
    • Mechanism linking absent heme synthesis to cytoplasmic iron mislocalization not resolved
    • Mouse model may not fully recapitulate human XLSA
  6. 2003 Medium

    Identified the proximal promoter as an essential erythroid regulatory element by showing a point mutation that collapses both reporter activity and patient mRNA.

    Evidence Luciferase reporter assays in K562 cells and RT-PCR of patient erythroid precursors

    PMID:12663458

    Open questions at the time
    • Disrupted transcription factor identity not confirmed
    • Promoter vs enhancer hierarchy not addressed
  7. 2008 High

    Revealed a gain-of-function mechanism by showing C-terminal frameshift deletions markedly increase enzyme activity, defining the C-terminus as an autoinhibitory element and the molecular basis of X-linked protoporphyria.

    Evidence Prokaryotic expression of two patient deletion mutants with in vitro activity assays

    PMID:18760763

    Open questions at the time
    • Structural basis of autoinhibition not resolved at this stage
    • Did not test effect on partner binding
  8. 2011 Medium

    Refined the gain-of-function model by attributing increased activity of a C-terminal mutant to accelerated product (5-ALA) release, and systematically separated catalytic from stability-based XLSA mechanisms.

    Evidence Recombinant enzyme assays of Y586F for product release; E. coli expression of ten missense mutants under varied PLP/thermal conditions

    PMID:21309041 PMID:21653323

    Open questions at the time
    • Y586F result is single mutation, single study
    • Product release kinetics not linked to structural changes
  9. 2012 High

    Mapped the SUCLA2 interaction to ALAS2 C-terminal residues and dissociated SUCLA2 binding from intrinsic catalysis, showing that loss of partner binding alone can cause XLSA while retained binding accompanies XLP gain-of-function.

    Evidence SUCLA2 affinity column binding, enzyme kinetics, and recombinant XLSA/XLP variants

    PMID:22740690

    Open questions at the time
    • In vivo requirement of SUCLA2 binding for heme output not directly tested
    • Structure of the C-terminal/SUCLA2 interface unknown
  10. 2013 High

    Identified the intron 1 GATA1-binding enhancer as essential for erythroid ALAS2 expression and a site of loss-of-function disease mutations.

    Evidence ChIP, EMSA, and luciferase reporter assays in K562 cells

    PMID:23935018

    Open questions at the time
    • In vivo necessity not yet established at this point
    • Composition of the bound complex undefined
  11. 2015 Medium

    Demonstrated additional regulatory layers: PLP-binding-impairing mutations drive cell-nonautonomous loss of mutant erythroid precursors, and miR-218 directly represses ALAS2 via its 3'-UTR to control erythroid differentiation.

    Evidence PLP binding and X-inactivation analysis (Y365C); 3'-UTR reporter and miRNA overexpression with ALAS2 knockdown in K562 cells

    PMID:25705881 PMID:26703568

    Open questions at the time
    • miR-218 regulation shown in cell line only
    • Physiological context driving miR-218 expression not defined
  12. 2016 High

    Established the in vivo essentiality and spatial organization of ALAS2 transcriptional control, showing the intron 1 GATA site anchors a long-range chromatin loop with a defined enhancer complex and is required for survival.

    Evidence Transgenic and CRISPR/Cas9 deletion in mice, chromatin loop analysis, and ChIP for GATA1/TAL1/LMO2/LDB1/Pol II

    PMID:28123038

    Open questions at the time
    • Relative contribution of int-8-GATA site partly defined
    • Loop dynamics during erythroid maturation not detailed
  13. 2017 Low

    Inferred that ALAS2 homodimerization is required for function from a frameshift variant predicted to yield a monomer.

    Evidence Sanger sequencing with SWISS-model structural prediction

    PMID:28731922

    Open questions at the time
    • Dimerization state inferred computationally, not experimentally validated
    • No functional assay of the variant protein
  14. 2020 Low

    Linked ALAS2 activity to downstream mitochondrial quality-control gene expression via heme-dependent transcription factor signaling rather than direct interaction.

    Evidence shRNA knockdown in K562 cells with qRT-PCR, Western blot, flow cytometry, and negative ALAS2-BNIP3L co-IP

    PMID:33067979

    Open questions at the time
    • Heme-GATA1/Nrf2-BNIP3L axis not reconstituted
    • Single cell-line model, no in vivo validation
  15. 2024 Medium

    Resolved that C-terminal loss-of-function variants cause disease through heterogeneous kinetic mechanisms (stability, substrate binding, cooperativity) without gross structural disruption.

    Evidence In vitro stability, PLP binding, substrate kinetics, and structural modeling of V562A and M567I

    PMID:38888931

    Open questions at the time
    • Single lab, no replication
    • In vivo correlation with patient phenotypes not established
  16. 2025 Medium

    Identified product (heme) feedback inhibition of mature ALAS2 as a regulatory mechanism, with heme acting as a reversible mixed inhibitor that locks the enzyme inactive.

    Evidence In vitro inhibition and heme-binding assays with structure-based modeling (preprint)

    PMID:bio_10.1101_2025.06.09.658730

    Open questions at the time
    • Preprint, single lab, not independently replicated
    • Heme-interacting regions identified by modeling, not experimentally mapped

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the autoinhibitory C-terminus, SUCLA2 association, and heme feedback are structurally integrated to set ALAS2 activity in vivo remains unresolved.
  • No high-resolution structure of human ALAS2 with C-terminus, SUCLA2, or bound heme
  • Quantitative contribution of each regulatory layer to erythroid heme flux unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016740 transferase activity 4 GO:0016829 lyase activity 2
Localization
GO:0005739 mitochondrion 2
Pathway
R-HSA-74160 Gene expression (Transcription) 2 R-HSA-1430728 Metabolism 1
Partners
GATA1LDB1LMO2SUCLA2TAL1

Evidence

Reading pass · 20 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2000 ALAS2 (ALAS-E) physically interacts with the beta subunit of ATP-specific succinyl-CoA synthetase (SCS-betaA) in mitochondria. Yeast two-hybrid screening of a human bone marrow cDNA library identified SCS-betaA as an ALAS-E binding partner, confirmed by transient expression and co-immunoprecipitation. The interaction is isoform-specific (ALAS-E but not ALAS-N) and is disrupted by the D190V mutation associated with pyridoxine-refractory sideroblastic anemia, suggesting the complex promotes efficient succinyl-CoA utilization or mitochondrial translocation of ALAS-E. Yeast two-hybrid screen, co-immunoprecipitation with transient expression The Journal of clinical investigation High 10727444
2012 C-terminal residues of ALAS2 are required for binding to SUCLA2 (beta subunit of succinyl-CoA synthetase). XLSA mutations p.Met567Val and p.Ser568Gly, as well as a p.Phe557Ter truncation, have normal or enhanced in vitro enzymatic activity and stability but fail to bind a SUCLA2 affinity column, establishing that the C-terminal region mediates SUCLA2 interaction and that loss of this interaction causes disease. Conversely, gain-of-function XLP mutant p.Met567GlufsX2 retains SUCLA2 binding, linking SUCLA2 association to in vivo ALAS2 activity regulation. Additionally, XLSA mutations p.Arg452Cys and p.Arg452His had normal SUCLA2 binding but showed loss of positive cooperativity for succinyl-CoA, increased Km for succinyl-CoA, and reduced pyridoxal 5'-phosphate affinity. SUCLA2 affinity column binding assay, enzyme kinetics, in vitro expression and purification of recombinant proteins The Journal of biological chemistry High 22740690
2008 C-terminal frameshift deletions in ALAS2 (c.1706-1709 delAGTG and c.1699-1700 delAT) cause gain-of-function by markedly increasing ALAS2 enzymatic activity. Prokaryotic expression of both mutant proteins demonstrated substantially elevated activity compared to wild-type, establishing that the 19-20 C-terminal residues normally suppress enzyme activity and that their removal or replacement leads to protoporphyrin overproduction causing X-linked dominant protoporphyria. Prokaryotic expression of mutant proteins, in vitro enzyme activity assay American journal of human genetics High 18760763
1994 The F165L missense mutation in ALAS2, found in Cooley's original XLSA family, reduces enzymatic specific activity to ~26% of normal after prokaryotic expression and affinity purification. Pyridoxal 5'-phosphate (PLP) activates and/or stabilizes the purified F165L mutant enzyme in vitro, consistent with pyridoxine responsiveness in vivo. The mutation resides in a highly conserved domain of the ALAS2 catalytic core. Prokaryotic expression, affinity purification, in vitro enzyme activity assay, PLP stabilization assay Blood High 7949148
1995 Missense mutations K299Q and A172T in ALAS2 cause thermolabile enzyme with decreased in vitro stability. Addition of pyridoxal 5'-phosphate in vitro stabilizes both mutant recombinant enzymes, consistent with the dramatic clinical response to pyridoxine observed in patients. The A172T mutation also resulted in decreased bone marrow delta-aminolevulinate synthase activity. In vitro recombinant enzyme expression, thermostability assay, PLP stabilization assay The Journal of clinical investigation High 7560104
2019 Systematic in vitro characterization of ALAS2 C-terminal truncation mutants (p.P561X, p.V562X, p.H563X, p.E569X, p.F575X) showed 1.4- to 5.6-fold increases in Vmax for both succinyl-CoA and glycine substrates with only modest Km changes, establishing that the C-terminal region normally constrains enzyme activity. Thermostabilities of truncated mutants were significantly lower than wild-type with an inverse relationship to Vmax fold-increase, suggesting that increased molecular flexibility/active site openness is the mechanism of gain-of-function. Five ALAS2 SNVs (p.R559H, p.E565D, p.R572C, p.S573F, p.Y586F) showed modest 1.3- to 1.9-fold Vmax increases. Site-directed mutagenesis, prokaryotic expression, purification, enzyme kinetic assays, thermostability assays Molecular medicine (Cambridge, Mass.) High 30678654
2011 The ALAS2 Y586F gain-of-function mutation (c.1757 A>T in exon 11), affecting the penultimate C-terminal amino acid, significantly increases the rate of 5-aminolevulinate release compared to wild-type ALAS2, establishing that C-terminal residues regulate product release kinetics. In vitro enzyme activity assay of recombinant expressed mutant protein Blood Medium 21653323
2013 A 130-bp erythroid-specific enhancer in intron 1 of ALAS2 contains a GATA1-binding cis-element that is essential for erythroid expression. GATA1 binding to this element was confirmed by chromatin immunoprecipitation in vivo and EMSA in vitro; the enhancer increased ALAS2 promoter activity 10-15-fold in K562 cells. Loss-of-function mutations at the GATA-binding site abolish GATA1 binding and enhancer activity, causing congenital sideroblastic anemia. Chromatin immunoprecipitation (ChIP), EMSA, luciferase reporter assay in K562 cells Haematologica High 23935018
2016 The intron 1 GATA site (int-1-GATA) of ALAS2 is indispensable for erythroid expression in vivo. Mice with a 13-bp deletion including this site showed embryonic lethality due to severe anemia from absent ALAS2 expression. The int-1-GATA site forms a long-range chromatin loop anchoring the intron 8 GATA site and the proximal promoter, with an enhancer complex including GATA1, TAL1, LMO2, LDB1 and Pol II. CRISPR/Cas9-mediated deletion confirmed the int-1-GATA site is more essential than the int-8-GATA site. Transgenic mouse deletion, CRISPR/Cas9 site-specific deletion, chromatin loop analysis, ChIP Nucleic acids research High 28123038
2003 A C-to-G transversion at nucleotide -206 of the ALAS2 proximal promoter reduces reporter activity by 94% in K562 erythroid cells and decreases ALAS2 mRNA by 87% in patient erythroid precursors, identifying the proximal promoter region as an important erythroid regulatory element. The mutation disrupts putative transcription factor binding sites. Luciferase reporter assay in K562 cells, RT-PCR quantification of mRNA in patient erythroid precursors Blood Medium 12663458
2002 ALAS2 deficiency in definitive erythroblasts (from Alas2-null ES cells differentiated in culture) results in 15-fold excess non-heme iron accumulation localized to the cytoplasm (not mitochondria) and increased lipid peroxidation, without interfering with erythroid cell development morphology or erythroid gene expression. This establishes that ALAS2 activity is required to prevent cytoplasmic iron overload and oxidative stress in erythroblasts. Alas2-null embryonic stem cell differentiation, electron microscopy for iron localization, iron quantification, lipid peroxidation assay Blood High 12393610
1998 The R411C missense mutation in ALAS2 reduces enzyme activity to 12% of wild-type in the absence of PLP and 25% in the presence of PLP, as determined by prokaryotic expression and purification. This establishes the mechanistic basis for pyridoxine responsiveness at this residue. Prokaryotic expression, enzyme purification, in vitro activity assay with and without PLP British journal of haematology Medium 9858242
2011 Ten ALAS2 missense mutations expressed in E. coli showed that five caused decreased enzymatic activity under standard conditions, and two had normal activity under standard conditions but showed reduced activity without exogenous PLP and increased thermosensitivity, revealing that some XLSA mutations affect PLP-dependent enzyme stability rather than direct catalytic mechanism. Prokaryotic expression in E. coli, in vitro ALAS2 enzymatic activity assay, thermosensitivity assay Human mutation Medium 21309041
2015 The ALAS2 Y365C mutation impairs binding of the essential cofactor pyridoxal 5'-phosphate, resulting in enzyme destabilization and loss of function. In erythroid cells and reticulocytes from affected females, complete skewing toward expression of the WT allele (but not in leukocytes) demonstrates cell-nonautonomous effects on erythropoiesis through apoptosis of erythroid precursors expressing the mutant allele. In vitro PLP binding assay, X-inactivation analysis in reticulocytes vs. leukocytes, primary erythroid cultures The Journal of clinical investigation Medium 25705881
2024 ALAS2 C-terminal loss-of-function variants V562A and M567I do not cause gross structural perturbations but V562A has decreased enzyme stability. PLP addition moderately increases stability of both variants. V562A shows enhanced in vitro activity but reduced succinyl-CoA binding efficiency, while M567I significantly alters cooperativity of substrate binding, establishing that C-terminal mutations can cause disease through distinct kinetic mechanisms. In vitro enzyme characterization, stability assays, PLP binding, substrate kinetics, structural modeling Biochemistry Medium 38888931
2015 miR-218 directly targets and represses ALAS2 expression by binding to the 3'-UTR of ALAS2 mRNA, as shown by 3'-UTR reporter assays. miR-218 overexpression in K562 cells phenocopies ALAS2 knockdown, inhibiting erythroid differentiation and altering iron metabolism. 3'-UTR luciferase reporter assay, miRNA overexpression, ALAS2 knockdown in K562 cells International journal of molecular sciences Medium 26703568
2017 A novel g.55040074delT deletion in exon 10 of ALAS2, predicted to generate a monomeric protein rather than the wild-type homodimer based on Swiss-model structural prediction, causes severe sideroblastic anemia, establishing that ALAS2 homodimerization is required for function. Sanger sequencing, SWISS-model protein structure prediction Journal of pediatric hematology/oncology Low 28731922
2020 ALAS2 knockdown in K562 cells leads to downregulation of BNIP3L (a mitophagy receptor) at both mRNA and protein levels, impaired erythroid differentiation (reduced CD71/CD235a markers after hemin induction), decreased ROS levels, and increased mitochondrial membrane potential. No direct physical interaction between ALAS2 and BNIP3L was detected by co-immunoprecipitation. The regulatory axis appears to work through intracellular heme levels affecting GATA1 and Nrf2 transcription factors. Lentiviral shRNA knockdown, qRT-PCR, Western blot, flow cytometry (erythroid differentiation markers, mitochondrial membrane potential, ROS), co-immunoprecipitation (negative result for direct binding) Zhongguo shi yan xue ye xue za zhi Low 33067979
2025 Mature human ALAS2 in the mitochondrial matrix is subject to negative feedback by heme binding. Heme binds ALAS2 with high affinity and acts as a reversible mixed inhibitor that reduces enzymatic activity. Structure-based modeling identifies two flexible regions of ALAS2 that interact with heme, locking the enzyme in an inactive conformation and occluding the active site. In vitro enzyme inhibition assay, heme binding affinity measurement, structure-based computational modeling bioRxivpreprint Medium bio_10.1101_2025.06.09.658730
1995 A G290S missense mutation (exon 7, nucleotide 871 G-to-A) in ALAS2 causes a marked decrease in enzymatic activity of the mutant protein expressed in a heterologous system, establishing the catalytic importance of this glycine residue in the enzyme. PCR amplification and sequencing, heterologous expression of mutant cDNA with enzymatic activity assay Human genetics Low 7705839

Source papers

Stage 0 corpus · 62 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2008 C-terminal deletions in the ALAS2 gene lead to gain of function and cause X-linked dominant protoporphyria without anemia or iron overload. American journal of human genetics 218 18760763
1995 Late-onset X-linked sideroblastic anemia. Missense mutations in the erythroid delta-aminolevulinate synthase (ALAS2) gene in two pyridoxine-responsive patients initially diagnosed with acquired refractory anemia and ringed sideroblasts. The Journal of clinical investigation 86 7560104
1994 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 81 7949148
2013 Identification of a novel erythroid-specific enhancer for the ALAS2 gene and its loss-of-function mutation which is associated with congenital sideroblastic anemia. Haematologica 77 23935018
2000 Interaction between succinyl CoA synthetase and the heme-biosynthetic enzyme ALAS-E is disrupted in sideroblastic anemia. The Journal of clinical investigation 77 10727444
2011 ALAS2 acts as a modifier gene in patients with congenital erythropoietic porphyria. Blood 65 21653323
1999 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 63 10029606
2011 Sideroblastic anemia: molecular analysis of the ALAS2 gene in a series of 29 probands and functional studies of 10 missense mutations. Human mutation 59 21309041
1992 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 56 1577484
2002 Aberrant iron accumulation and oxidized status of erythroid-specific delta-aminolevulinate synthase (ALAS2)-deficient definitive erythroblasts. Blood 50 12393610
2013 X-linked sideroblastic anemia due to ALAS2 intron 1 enhancer element GATA-binding site mutations. American journal of hematology 44 24166784
2012 X-linked sideroblastic anemia due to carboxyl-terminal ALAS2 mutations that cause loss of binding to the β-subunit of succinyl-CoA synthetase (SUCLA2). The Journal of biological chemistry 42 22740690
2015 X-linked macrocytic dyserythropoietic anemia in females with an ALAS2 mutation. The Journal of clinical investigation 41 25705881
2006 X-linked sideroblastic anemia associated with a novel ALAS2 mutation and unfortunate skewed X-chromosome inactivation patterns. Blood cells, molecules & diseases 40 16735131
2016 Intron 1 GATA site enhances ALAS2 expression indispensably during erythroid differentiation. Nucleic acids research 38 28123038
2014 In ferrochelatase-deficient protoporphyria patients, ALAS2 expression is enhanced and erythrocytic protoporphyrin concentration correlates with iron availability. Blood cells, molecules & diseases 37 25179834
2003 A promoter mutation in the erythroid-specific 5-aminolevulinate synthase (ALAS2) gene causes X-linked sideroblastic anemia. Blood 37 12663458
2022 METTL3-modified lncRNA-SNHG8 binds to PTBP1 to regulate ALAS2 expression to increase oxidative stress and promote myocardial infarction. Molecular and cellular biochemistry 36 36282350
1992 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. Human molecular genetics 32 1301172
1995 A new mutation of the ALAS2 gene in a large family with X-linked sideroblastic anemia. Human genetics 31 7705839
2022 Congenital sideroblastic anemia model due to ALAS2 mutation is susceptible to ferroptosis. Scientific reports 22 35637209
2019 Molecular expression, characterization and mechanism of ALAS2 gain-of-function mutants. Molecular medicine (Cambridge, Mass.) 20 30678654
1998 R411C mutation of the ALAS2 gene encodes a pyridoxine-responsive enzyme with low activity. British journal of haematology 19 9858242
2002 Absent phenotypic expression of X-linked sideroblastic anemia in one of 2 brothers with a novel ALAS2 mutation. Blood 18 12393718
2021 Muscle atrophy induced by overexpression of ALAS2 is related to muscle mitochondrial dysfunction. Skeletal muscle 17 33785075
2017 Non syndromic childhood onset congenital sideroblastic anemia: A report of 13 patients identified with an ALAS2 or SLC25A38 mutation. Blood cells, molecules & diseases 16 28772256
1994 Pyridoxine-refractory congenital sideroblastic anaemia with evidence for autosomal inheritance: exclusion of linkage to ALAS2 at Xp11.21 by polymorphism analysis. Journal of medical genetics 16 7912287
2015 MiR-218 Inhibits Erythroid Differentiation and Alters Iron Metabolism by Targeting ALAS2 in K562 Cells. International journal of molecular sciences 14 26703568
2006 Disparate phenotypic expression of ALAS2 R452H (nt 1407 G --> A) in two brothers, one with severe sideroblastic anemia and iron overload, hepatic cirrhosis, and hepatocellular carcinoma. Blood cells, molecules & diseases 13 16540354
2005 Iron overload in an African American woman with SS hemoglobinopathy and a promoter mutation in the X-linked erythroid-specific 5-aminolevulinate synthase (ALAS2) gene. Blood cells, molecules & diseases 13 15885606
2006 Three kinships with ALAS2 P520L (c. 1559 C --> T) mutation, two in association with severe iron overload, and one with sideroblastic anemia and severe iron overload. Blood cells, molecules & diseases 11 16446107
2004 Nucleotide variation at Msn and Alas2, two genes flanking the centromere of the X chromosome in humans. Genetics 11 15166166
2016 Sideroblastic anemia: functional study of two novel missense mutations in ALAS2. Molecular genetics & genomic medicine 10 27247955
2014 X-linked sideroblastic anaemia due to ALAS₂ mutations in the Netherlands: a disease in disguise. The Netherlands journal of medicine 10 24829177
2008 Multi-organ iron overload in an African-American man with ALAS2 R452S and SLC40A1 R561G. Acta haematologica 10 19066423
2023 Protective effects of electroacupuncture on polycystic ovary syndrome in rats: Down-regulating Alas2 to inhibit apoptosis, oxidative stress, and mitochondrial dysfunction in ovarian granulosa cells. Tissue & cell 7 37075681
2014 Concomitant a novel ALAS2 mutation and GATA1 mutation in a newborn: a case report and review of the literature. American journal of blood research 7 25232504
2024 Rapid detection of blood using a novel application of RT-RPA integrated with CRISPR-Cas: ALAS2 detection as a model. Forensic science international. Genetics 6 39089060
2020 A Novel ALAS2 Missense Mutation in Two Brothers With Iron Overload and Associated Alterations in Serum Hepcidin/Erythroferrone Levels. Frontiers in physiology 6 33281618
2024 ALAS2 overexpression alleviates oxidative stress-induced ferroptosis in aortic aneurysms via GATA1 activation. Journal of thoracic disease 5 38738239
2020 X-linked dominant protoporphyria in a Chinese pedigree reveals a four-based deletion of ALAS2. Annals of translational medicine 5 32355788
2002 A novel mutation in exon 5 of the ALAS2 gene results in X-linked sideroblastic anemia. Clinica chimica acta; international journal of clinical chemistry 5 12031592
2023 Severe Microcytic Anemia Caused by Complex Hereditary Spherocytosis and X-Linked Sideroblastic Anemia with Mutations in SPTB and ALAS2 Genes. Journal of clinical medicine 4 36902777
2024 Elucidating the Role of Human ALAS2 C-terminal Mutations Resulting in Loss of Function and Disease. Biochemistry 3 38888931
2020 [Knockdown of ALAS2 Affects Erythroid Differentiation by Down-regulating Mitophagy Receptor BNIP3L]. Zhongguo shi yan xue ye xue za zhi 3 33067979
2014 [Congenital sideroblastic anemia-a new family with identification of K156E mutation of ALAS2 gene and literature review]. Zhonghua xue ye xue za zhi = Zhonghua xueyexue zazhi 3 24606657
2025 The role of genetic testing in accurate diagnosis of X-linked sideroblastic anemia: novel ALAS2 mutations and the impact of X-chromosome inactivation. Scientific reports 2 40195342
2021 A hemizygous p.R204Q mutation in the ALAS2 gene underlies X-linked sideroblastic anemia in an adult Chinese Han man. BMC medical genomics 2 33858445
2017 A Novel ALAS2 Mutation Resulting in Variable Phenotypes and Pyridoxine Response in a Family with X-linked Sideroblastic Anemia. Annals of clinical and laboratory science 2 28667034
2000 [A novel mutation of the ALAS2 gene in a family with X-linked sideroblastic anemia]. Zhonghua xue ye xue za zhi = Zhonghua xueyexue zazhi 2 11877024
2026 ALAS2 Prevents Neonatal Necrotizing Enterocolitis by Improving Ferroptosis in Intestinal Epithelial Cells Through Inhibition of Oxidative Stress. Mediators of inflammation 1 41509986
2025 X-Linked Sideroblastic Anemia Induced by a Novel ALAS2 Nonsense Mutation: A Case Report and Literature Review. Annals of clinical and laboratory science 1 41253474
2024 A novel and apparent de novo ALAS2 missense variant associated with congenital sideroblastic anemia. Frontiers in pediatrics 1 39281190
2018 [Successful treatment of X-linked sideroblastic anemia with ALAS2 R452H mutation using vitamin B6]. [Rinsho ketsueki] The Japanese journal of clinical hematology 1 29743399
2017 X-linked Sideroblastic Anemia in a Malay Boy With ALAS2 S568G Mutation. Journal of pediatric hematology/oncology 1 28644307
2017 A Novel g.55040074delT in ALAS2 Gene Resulting in a Monomeric Protein and Severe Sideroblastic Anemia Phenotype. Journal of pediatric hematology/oncology 1 28731922
2026 The neuronal ALAS2/5-ala axis mitigates chemotherapy-induced neurotoxicity via the BACH1/NRF2 pathway. British journal of pharmacology 0 41652971
2026 A case report of congenital sideroblastic anemia caused by a novel ALAS2 mutation in conjunction with thalassemia. Annals of hematology 0 41961321
2025 Case report: A novel 11-bp deletion in exon 11 causing a frameshift in the C-terminal of the ALAS2 gene leading to X-linked sideroblastic anemia-a family study. Frontiers in medicine 0 39995829
2025 X-Linked Sideroblastic Anaemia Caused by Intronic ALAS2 Variant Resulting in Highly Variable Expressive Phenotype in Male Siblings, a Case Report. EJHaem 0 40391332
2025 Hypoxia impairs monocyte/macrophage function and host defense via ALAS2-mediated heme biosynthesis in Japanese sea bass (Lateolabrax japonicus). Developmental and comparative immunology 0 41407058
2004 [Construction of recombinant vector expressing ALAS2 gene in X-linked sideroblastic anemia]. Zhongguo shi yan xue ye xue za zhi 0 15498136

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