Hereditary spherocytosis with band 3 deficiency. Association with a nonsense mutation of the band 3 gene (allele Lyon), and aggravation by a low-expression allele occurring in trans (allele Genas).
We describe an 18-year-old with moderate hereditary spherocytosis. The condition was associated with a 35% decrease in band 3. The underlying mutation was Arg to stop at codon 150 (CGA-->TGA) and was designated R150X, which defined allele Lyon of the EPB3 gene. The inheritance pattern was dominant. However, the mother, who also carried the allele Lyon, had a milder clinical presentation and only a 16% decrease of band 3. We suggested that the father had transmitted a modifying mutation that remained silent in the heterozygous state. Nucleotide sequencing after single strand conformation polymorphism analysis of the band 3 cDNA and promoter region revealed a G-->A substitution at position 89 from the cap site in the 5'-untranslated region, designated 89G-->A, which defined allele Genas. A ribonuclease protection assay showed that (1) the allele Genas (father) resulted in a 33% decrease in the amount of band 3 mRNA, (2) the reduction caused by the allele Lyon (mother) was 42%, and (3) the compound heterozygous state for both alleles (proband) resulted in a 58% decrease. These results suggest that some mildly deleterious alleles of the EPB3 gene are compensated for by the normal allele in the heterozygous state. They are shown through the aggravation of the clinical picture, based on more obvious molecular alterations when they occur in trans to an allele causing a manifest reduction of band 3 membrane protein concentration.
Alloisio
N
N
Laboratoire de Gènètique Moléculaire Humaine, CNRS, URA 1171, Institut Pasteur de Lyon, France.
Maillet
P
P
Carré
G
G
Texier
P
P
Vallier
A
A
Baklouti
F
F
Philippe
N
N
Delaunay
J
J
D000483:Alleles; D001457:Anion Exchange Protein 1, Erythrocyte / Q000172:deficiency* / Q000235:genetics; D001483:Base Sequence; D006579:Heterozygote; D006801:Humans; D007223:Infant; D008297:Male; D008969:Molecular Sequence Data; D017354:Point Mutation; D018807:Polymorphism, Single-Stranded Conformational; D013103:Spherocytosis, Hereditary / Q000235:genetics*
D001457:Anion Exchange Protein 1, Erythrocyte