ANK1 and Hereditary Spherocytosis Type 1

ANK1 encodes erythrocyte ankyrin-1, a critical linker between the spectrin–actin cytoskeleton and the red blood cell membrane. Heterozygous loss-of-function variants in ANK1 underlie autosomal dominant hereditary spherocytosis type 1, characterized by hemolytic anemia and splenomegaly (HP:0001903, HP:0001744).

Genetic evidence includes at least 61 unrelated probands harboring 45 unique ANK1 variants (nonsense, frameshift, splicing, promoter) identified across multiple cohorts ([Front. Genet. 2020] PMID:33014018; [J. Cell. Mol. Med. 2019] PMID:31016877; [Clin. Genet. 2023] PMID:36203343). Segregation analyses demonstrate variant co-segregation in seven affected relatives, with six additional de novo events ([Front. Genet. 2023] PMID:36647015).

The variant spectrum comprises non-sense (e.g., c.290T>G (p.Leu97Arg)), frameshift (e.g., c.841C>T (p.Arg281Ter)), canonical splice-site and deep intronic mutations, and promoter defects (e.g., c.-153G>A), consistent with haploinsufficiency. No founder alleles have been reported, and recurrent de novo mutations suggest mutational hotspots.

Functional assays provide moderate concordance: promoter mutations reduce ANK1 transcription in vitro ([J. Biol. Chem. 2001] PMID:11527968), a mouse hypomorphic normoblastosis model recapitulates erythrocyte fragility via reduced ankyrin levels ([Hem. J. 2003] PMID:14671619), and minigene splicing assays confirm aberrant transcripts leading to nonsense-mediated decay ([Front. Genet. 2024] PMID:38655052).

No conflicting reports have been published. Taken together, the robust genetic and experimental data establish a definitive association between ANK1 and hereditary spherocytosis type 1, with haploinsufficiency as the primary disease mechanism. Key Take-home: ANK1 genetic testing enables accurate diagnosis and informs family-based management in hereditary spherocytosis.

References

• Frontiers in Genetics • 2020 • Genetic and Clinical Characteristics of Patients With Hereditary Spherocytosis in Hubei Province of China PMID:33014018
• Journal of Cellular and Molecular Medicine • 2019 • Two novel ANK1 loss-of-function mutations in Chinese families with hereditary spherocytosis PMID:31016877
• Clinical Genetics • 2023 • Identification of variants in 94 Chinese patients with hereditary spherocytosis by next-generation sequencing PMID:36203343
• The Journal of Biological Chemistry • 2001 • Erythrocyte ankyrin promoter mutations associated with recessive hereditary spherocytosis cause significant abnormalities in ankyrin expression PMID:11527968
• The Hematology Journal • 2003 • Normoblastosis, a murine model for ankyrin-deficient hemolytic anemia, is caused by a hypomorphic mutation in the erythroid ankyrin gene Ank1 PMID:14671619
• Frontiers in Genetics • 2024 • Identification of a novel ANK1 gene variant c.1504-9G>A and its mechanism of intron retention in hereditary spherocytosis PMID:38655052

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