Molecular pathology of haemoglobin H disease in Sardinians

Abstract

We investigated the molecular basis for haemoglobin H disease in 50 Sardinian patients by restriction endonuclease analysis. We found that the majority (78% of the cases) are due to gene deletion (--/-.alpha.). Among those with a combination of deletion and nondeletion defects (--/.alpha..alpha.th), the most prevalent nondeletion lesion (70% of the nondeletion defects) was the initiation codon mutation of the .alpha.2 gene (.alpha.Nco.alpha.), previously discovered in this population. Of the remaining patients with the (--/.alpha..alpha.th) genotype, two showed the IVS-1 splice junction lesion and one a mutation in the .alpha.1 gene, removing the Nco I site within the 5'' part of the .alpha.1 gene, which may arise from a process of gene conversion from the initiation codon mutant of the .alpha.2 gene. A single patient had the homozygous state for the initiation codon mutant of the .alpha.2 gene. Study of genotype-phenotype correlations indicates that the (.alpha.Nco.alpha.) haplotype is associated with a more severe defect in the .alpha.-globin chain output than that resulting from the (-.alpha.) haplotype. We may conclude that restriction endonuclease analysis is a powerful method for the definition of the molecular heterogeneity of haemoglobin H disease.