Coinheritance of two α‐spectrin gene defects in a recessive spherocytosis family

D Dhermy, J Steen‐Johnsen, O Bournier… - Clinical & Laboratory …, 2000 - Wiley Online Library
D Dhermy, J Steen‐Johnsen, O Bournier, G Hetet, T Cynober, G Tchernia, B Grandchamp
Clinical & Laboratory Haematology, 2000Wiley Online Library
We studied a recessive hereditary spherocytosis (HS) family from Norway in which all four
children had haemolytic spherocytosis while spectrin (Sp) deficiency was detected in the
proband. Molecular analysis demonstrated that all affected children had inherited the low
expression α‐Sp allele LEPRA (Low Expressed PRAgue) from the father. Haplotyping with a
polymorphic dinucleotide repeat for the α‐Sp gene (αVNTR) located in the 3′ untranslated
region of mRNA showed that all recessive children had inherited the same maternal α …
We studied a recessive hereditary spherocytosis (HS) family from Norway in which all four children had haemolytic spherocytosis while spectrin (Sp) deficiency was detected in the proband. Molecular analysis demonstrated that all affected children had inherited the low expression α‐Sp allele LEPRA (Low Expressed PRAgue) from the father. Haplotyping with a polymorphic dinucleotide repeat for the α‐Sp gene (αVNTR) located in the 3′ untranslated region of mRNA showed that all recessive children had inherited the same maternal α‐spectrin allele. The paternal Sp‐αLEPRA allele was found in cis of the polymorphic α‐Sp Bughill allele (αBH) characterized by the A970D point mutation in the Sp α‐chain. This mutation was identified on two‐dimensional electrophoresis of Sp tryptic digests as an acidic shift of the αII tryptic domains (spots αIIa). Analyses of the relative expression of the paternal α‐Sp Bughill polymorphism in the proband showed that the product of the maternal α‐Sp gene is almost completely absent from the mature erythrocyte membrane. Comparative analysis between αVNTR PCR‐amplified from genomic DNA and from cDNA showed that the maternal low expression α‐Sp allele is associated with a decreased amount of mRNA. Results from molecular and biochemical studies showed that all the affected children of this family are compound heterozygous for two different low expression α‐Sp alleles: an uncharacterized defective α‐Sp allele on the maternal side and an αLEPRA allele tagged by the αIIa polymorphism on the paternal side.
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