MOLECULAR-BASIS AND HAPLOTYPING OF THE ALPHA-II DOMAIN POLYMORPHISMS OF SPECTRIN - APPLICATION TO THE STUDY OF HEREDITARY ELLIPTOCYTOSIS AND PYROPOIKILOCYTOSIS

Hereditary elliptocytosis (HE) and hereditary pyropoikilocytosis (HPP) are inherited disorders of erythrocyte shape that are frequently asso ciated with abnormalities in alpha-spectrin, one of the principal stru ctural proteins of the erythrocyte membrane skeleton. Five polymorphis ms of the alpha-spectrin gene, located in a 6-kb interval of genomic D NA, were identified and analyzed in normal and mutant alpha-spectrin a lleles. Three of these polymorphisms are due to single nucleotide subs titutions in the alpha-spectrin gene coding region that lead to change s in the amino acid sequence. In combination, these three polymorphism s are responsible for the different peptide phenotypes of the alpha II domain previously observed following limited tryptic digestion of spe ctrin protein. The most common haplotype, type 1, was found predominan tly in Caucasians and was the only haplotype identified in Asians. Hap lotypes 2, 3, and 4 were identified predominantly in individuals of Af rican ancestry and were commonly found in patients with HE or HPP. Ana lysis of coinheritance of all domain polymorphisms with alpha-spectrin gene mutations causing HE or HPP in African-American patients with HE and HPP suggests that, with one exception, a given HE/HPP mutation is present in an alpha-spectrin gene of only one haplotype, indicating a founder effect. The other two polymorphisms located in this region of the alpha-spectrin gene do not change the amino acid sequence of the encoded alpha-spectrin chain and are not in linkage disequilibrium wit h three of the four ail domain haplotypes. A model is proposed for the evolutionary origin of the different haplotypes.