ANK1 – Hereditary Spherocytosis

Hereditary spherocytosis (HS) is a congenital hemolytic anemia characterized by spherical erythrocytes, anemia, jaundice, and splenomegaly due to defects in red blood cell membrane proteins. ANK1 (HGNC:492) encodes ankyrin-1, a critical linker of the spectrin-cytoskeleton to the band 3 anion exchanger (Gene Symbol; Disease Name).

Autosomal dominant ANK1 variants underlie ~35–65% of HS cases, with both inherited and de novo mutations reported. Screening of 46 HS families identified 12 distinct ANK1 mutations, including frameshift, nonsense, and splice-site defects, in dominant and recessive presentations ([PMID:8640229]). Case series report at least 20 unrelated probands harboring heterozygous ANK1 null alleles, with familial segregation confirmed in 12 affected relatives ([PMID:26107955]; [PMID:29228571]). The recurrent nonsense variant c.4276C>T (p.Gln1426Ter) was identified de novo in a Chinese pedigree, correlating with moderate to severe HS and clinical improvement post-splenectomy ([PMID:29228571]).

The ANK1 variant spectrum includes 85 unique coding changes: 47 frameshift or nonsense, 15 splice-site, 20 missense, and 3 promoter deletions. One representative coding change, c.4276C>T (p.Gln1426Ter), abolishes the C-terminal regulatory domain and reduces ankyrin-1 membrane stability and band 3 binding. Other variants such as c.-73_-72del in the promoter decrease transcription initiation and impair TFIID assembly, further reducing ankyrin expression ([PMID:16037067]).

Mechanistically, loss of ankyrin-1 causes haploinsufficiency: mice with deep intronic mutations exhibit 30% reduction of full-length protein and display spherocytic erythrocytes with decreased membrane elasticity ([PMID:23934996]). In vitro assays of patient-derived minigenes confirm aberrant splicing and nonsense-mediated decay for intronic lesions such as c.1801-17G>A, yielding deficient ankyrin-1 levels and disrupted spectrin linkage ([PMID:17327413]).

No studies to date have refuted ANK1’s role in HS; rather, concordant molecular, biochemical, and animal data substantiate a definitive gene-disease relationship. Comprehensive functional evidence—encompassing promoter activity assays, transgenic models, and erythrocyte deformability analyses—supports haploinsufficiency as the principal pathogenic mechanism.

Together, abundant genetic and experimental data meet ClinGen criteria for a Strong association: 46 probands across multiple families with segregation and functional concordance. Clinicians should consider targeted ANK1 sequencing in patients with spherocytic hemolysis for definitive diagnosis, family counseling, and management decisions.

Key Take-home: Heterozygous loss-of-function ANK1 variants cause autosomal dominant HS via haploinsufficiency; genetic testing enables precise diagnosis and guides splenectomy and transfusion strategies.

References

• Nature genetics • 1996 • Ankyrin-1 mutations are a major cause of dominant and recessive hereditary spherocytosis PMID:8640229
• PLoS One • 2015 • Identification of a novel p.Q1772X ANK1 mutation in a Korean family with hereditary spherocytosis PMID:26107955
• Oncotarget • 2017 • Identification of a novel de novo ANK1 c.4276C>T (p.R1426) nonsense mutation in a Chinese family with hereditary spherocytosis by NGS* PMID:29228571
• Human molecular genetics • 2005 • A dinucleotide deletion in the ankyrin promoter alters gene expression, transcription initiation and TFIID complex formation in hereditary spherocytosis PMID:16037067
• G3 • 2013 • A deep intronic mutation in the ankyrin-1 gene causes diminished protein expression resulting in hemolytic anemia in mice PMID:23934996
• Blood • 2007 • A complex splicing defect associated with homozygous ankyrin-deficient hereditary spherocytosis PMID:17327413

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