ALAS2 – X-linked erythropoietic protoporphyria

X-linked erythropoietic protoporphyria (XLDPP) is a rare porphyria characterized by a gain-of-function in erythroid heme biosynthesis leading to markedly elevated erythrocyte protoporphyrin levels, severe cutaneous photosensitivity, and risk of liver dysfunction. The causative gene, ALAS2, encodes the erythroid-specific 5-aminolevulinate synthase. Pathogenic variants cluster in exon 11, the C-terminal regulatory region, and act through increased enzyme activity and altered protein interactions.

Inheritance of XLDPP is X-linked dominant, with hemizygous males and heterozygous females both variably affected due to X-chromosomal inactivation. C-terminal frameshift deletions c.1706_1709del (p.Glu569GlyfsTer24) and c.1699_1700del (p.Met567fs) have been reported in eight unrelated families with segregation of disease in >15 individuals ([PMID:18760763]). A four-base deletion segregating in a Chinese pedigree further confirms this pattern ([PMID:32355788]).

Variant spectrum includes recurrent exon 11 frameshifts, missense substitutions (e.g., p.R559H, p.E565D) identified in population sequencing, and founder alleles. Functional single-nucleotide variants from Exome Sequencing Project (p.R559H, p.S573F, p.Y586F) and novel truncations (p.P561Ter, p.V562Ter) demonstrate increased Vmax (1.3–5.6-fold) and thermostability ([PMID:30678654]). The C-terminal cluster spans residues 533–580.

Functional evidence supports a gain-of-function mechanism. Prokaryotic expression of ΔAT and ΔAGTG mutants showed 20–40-fold increases in specific activity ([PMID:23348515]). Binding assays reveal altered interaction with the SUCLA2 β-subunit, modulating enzyme cooperativity and vitamin B6 affinity ([PMID:22740690]). Heterozygous females exhibit phenotype variability correlating with X-chromosomal inactivation patterns ([PMID:25615817]).

No studies dispute the ALAS2–XLDPP association. Loss-of-function ALAS2 variants cause X-linked sideroblastic anemia, distinct from the gain-of-function porphyria phenotype.

Collectively, genetic and experimental data fulfill ClinGen criteria for a Strong gene–disease association. Testing of ALAS2 exon 11 should be integral to the diagnostic workup of unexplained porphyria, enabling precision diagnosis and family counseling.

Key Take-home: C-terminal exon 11 gain-of-function mutations in ALAS2 reliably predict XLDPP, guiding targeted genetic testing and management.

References

• American Journal of Human Genetics • 2008 • C-terminal deletions in the ALAS2 gene lead to gain of function and cause X-linked dominant protoporphyria without anemia or iron overload PMID:18760763
• Annals of Translational Medicine • 2020 • X-linked dominant protoporphyria in a Chinese pedigree reveals a four-based deletion of ALAS2 PMID:32355788
• Molecular Medicine (Cambridge, Mass.) • 2019 • Molecular expression, characterization and mechanism of ALAS2 gain-of-function mutants PMID:30678654
• Journal of Biological Chemistry • 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) PMID:22740690
• Clinical Genetics • 2016 • X-chromosomal inactivation directly influences the phenotypic manifestation of X-linked protoporphyria PMID:25615817

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