MOLECULAR-BASIS AND HAPLOTYPING OF THE ALPHA-II DOMAIN POLYMORPHISMS OF SPECTRIN - APPLICATION TO THE STUDY OF HEREDITARY ELLIPTOCYTOSIS AND PYROPOIKILOCYTOSIS
Pg. Gallagher et al., MOLECULAR-BASIS AND HAPLOTYPING OF THE ALPHA-II DOMAIN POLYMORPHISMS OF SPECTRIN - APPLICATION TO THE STUDY OF HEREDITARY ELLIPTOCYTOSIS AND PYROPOIKILOCYTOSIS, American journal of human genetics, 59(2), 1996, pp. 351-359
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.