ABCB7 and X-linked sideroblastic anemia with ataxia

X-linked sideroblastic anemia with ataxia (XLSA-A) is a rare X-linked recessive disorder characterized by early onset cerebellar ataxia and mild sideroblastic anemia due to impaired mitochondrial iron homeostasis. The causative gene, ABCB7, encodes a mitochondrial ATP-binding cassette transporter essential for the export of a factor required for cytosolic iron-sulfur (Fe-S) protein maturation. Hemizygous loss-of-function or missense mutations in ABCB7 lead to accumulation of mitochondrial iron and defective Fe-S enzyme activities in erythroid and neural tissues, underpinning the dual hematological and neurological manifestations.

Genetic evidence for ABCB7 in XLSA-A derives from five unrelated families harboring distinct missense mutations ([PMID:22398176], [PMID:34354969]). Initially, three pedigrees were reported with unique ABCB7 substitutions; a fourth family was described carrying c.624A>T (p.Glu208Asp) in exon 7, and a fifth (Chinese) family with c.2024A>G (p.Glu675Gly) was recently identified. All affected individuals are male and hemizygous; segregation analysis confirmed variant co-segregation in at least two affected brothers in the earliest report ([PMID:11050011]).

The variant spectrum in XLSA-A comprises predominantly missense changes that alter conserved residues within transmembrane or ATP-binding domains. Reported pathogenic alleles include c.624A>T (p.Glu208Asp) and c.2024A>G (p.Glu675Gly). No truncating or splice variants have been documented in XLSA-A patients to date, underscoring the critical role of single amino acid substitutions in transporter dysfunction.

Functional assays in yeast demonstrate that wild-type ABCB7 fully complements the growth and cytosolic Fe-S protein maturation defects of Δatm1 cells, whereas the p.Glu433Lys mutant and its yeast orthologue p.Asp398Lys exhibit severely reduced complementation efficiency, confirming a loss-of-function mechanism ([PMID:11050011]). Subsequent studies showed that mutant ABCB7 proteins fail to rescue cytosolic Fe-S enzyme activities, leading to mitochondrial iron overload.

An inducible Cre/loxP Abcb7 knockout in mice revealed an X-linked parent-of-origin lethality and essential requirement for ABCB7 in extra-embryonic tissues and multiple cell lineages. Tissue-specific deletions impaired cytosolic Fe-S cluster assembly and dysregulated iron regulatory protein 1, mirroring key aspects of human XLSA-A pathophysiology ([PMID:16467350]).

Collectively, five families with hemizygous ABCB7 missense mutations, supportive segregation, and concordant functional data from yeast and mouse models establish a Strong gene-disease association. The mechanism involves haploinsufficiency or dominant-negative effects on mitochondrial Fe-S cluster export, causing sideroblastic anemia and cerebellar ataxia. ABCB7 genetic testing provides definitive diagnosis and informs carrier screening in at-risk families.

References

• European journal of paediatric neurology • 2012 • X-linked sideroblastic anemia and ataxia: a new family with identification of a fourth ABCB7 gene mutation. PMID:22398176
• Frontiers in pediatrics • 2021 • The First Case Report of X-Linked Sideroblastic Anemia With Ataxia of Chinese Origin and Literature Review. PMID:34354969
• Blood • 2000 • Human ABC7 transporter: gene structure and mutation causing X-linked sideroblastic anemia with ataxia with disruption of cytosolic iron-sulfur protein maturation. PMID:11050011
• Human molecular genetics • 2006 • The mitochondrial ATP-binding cassette transporter Abcb7 is essential in mice and participates in cytosolic iron-sulfur cluster biogenesis. PMID:16467350

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