What mutations have been reported in hereditary spherocytosis?

Mutations Reported in Hereditary Spherocytosis

Hereditary spherocytosis results from mutations in five genes encoding red blood cell membrane proteins: ANK1 (ankyrin-1), SPTB (beta-spectrin), SPTA1 (alpha-spectrin), SLC4A1 (band 3/anion exchanger 1), and EPB42 (protein 4.2), with ANK1 and SPTB mutations accounting for approximately 88% of cases in Chinese populations. 1

Gene-Specific Mutation Patterns

ANK1 (Ankyrin-1) Mutations

• Nonsense mutations account for approximately 36% (26/73) of ANK1 mutations 1
• Frameshift mutations represent approximately 27% (20/73) of ANK1 mutations 1
• Hotspot exons include exons 8,9,26, and 28 where mutations cluster 1
• ANK1 mutations account for approximately 46% of Chinese HS cases 1
• Mutations in the ANK1 death domain are associated with lower MCV and MCH levels compared to mutations in other ANK1 domains 2
• Inheritance is typically autosomal dominant (75%), though recessive cases occur 3

SPTB (Beta-Spectrin) Mutations

• Nonsense mutations are the most common type, representing approximately 48% (32/66) of SPTB mutations 1
• Frameshift mutations account for approximately 23% (15/66) of SPTB mutations 1
• Six frameshift and nonsense mutations have been documented to cause loss of heterozygosity at the cDNA level, reflecting absence of mutant mRNA transcripts 4
• Hotspot exons include exons 13,15, and 18-30 1
• SPTB mutations account for approximately 42% of Chinese HS cases 1
• Most mutations result in a mild to moderate autosomal dominant phenotype with conspicuous spherocytosis and 8-15% acanthocytes 4

SPTA1 (Alpha-Spectrin) Mutations

• SPTA1 mutations are rare, accounting for only approximately 1% of Chinese HS cases 1
• Recessive HS commonly results from compound heterozygosity involving a low expression allele paired with a missense mutation 5
• Defects often involve the promoter or 5'-untranslated region combined with missense mutations 5

SLC4A1 (Band 3) Mutations

• Missense mutations predominate, accounting for approximately 78% (14/18) of SLC4A1 mutations 1
• Mutations are scattered throughout the entire gene region without clear hotspots 1
• SLC4A1 mutations account for approximately 11% of Chinese HS cases 1
• Inheritance pattern is typically autosomal dominant 5

EPB42 (Protein 4.2) Mutations

• EPB42 mutations are extremely rare in Chinese populations, with no reported cases in comprehensive reviews 1
• When present, recessive HS results from compound heterozygosity of various mutations 5

Inheritance Patterns and Novel Findings

• Approximately 75% of HS cases follow autosomal dominant inheritance 3
• De novo mutations account for a significant proportion, with 6 out of 13 families in one study showing spontaneous mutations 2
• Variable expressivity has been documented even in identical twins carrying the same ANK1 c.341C>T variant 2
• Nearly every family has a unique mutation, with no single frequent defect identified 5

Molecular Consequences

• Most mutations result in no abnormal protein being present in red cells, as frameshift and nonsense mutations lead to mRNA degradation 5
• Defects disrupt vertical interactions between the membrane skeleton and lipid bilayer, causing loss of red cell surface area and spheroidal shape 3
• Rare missense mutations like ankyrin Walsrode (V463I) and beta-spectrin Kissimmee (W202R) have provided insight into functional protein domains 5