A common type of the spectrin alpha I 46-50a-kD peptide abnormality in hereditary elliptocytosis and pyropoikilocytosis is associated with a mutation distant from the …

PG Gallagher, WT Tse, T Coetzer… - The Journal of …, 1992 - Am Soc Clin Investig
PG Gallagher, WT Tse, T Coetzer, MC Lecomte, M Garbarz, HS Zarkowsky, A Baruchel
The Journal of clinical investigation, 1992Am Soc Clin Investig
We studied nine individuals from five unrelated families with alpha I/46-50a hereditary
elliptocytosis (HE) or hereditary pyropoikilocytosis (HPP), including one of the original HHP
probands first reported by Zarkowsky and colleagues (1975. Br. J. Haematol. 29: 537-543).
Biochemical analysis of erythrocyte membrane proteins from these patients revealed, as a
common abnormality, the presence of the alpha I/46-50a peptide after limited tryptic
digestion of spectrin. The polymerase chain reaction was utilized to study the structure of the …
We studied nine individuals from five unrelated families with alpha I/46-50a hereditary elliptocytosis (HE) or hereditary pyropoikilocytosis (HPP), including one of the original HHP probands first reported by Zarkowsky and colleagues (1975. Br. J. Haematol. 29:537-543). Biochemical analysis of erythrocyte membrane proteins from these patients revealed, as a common abnormality, the presence of the alpha I/46-50a peptide after limited tryptic digestion of spectrin. The polymerase chain reaction was utilized to study the structure of the DNA encoding the alpha I domain of spectrin in the affected individuals. The DNA sequence of the alpha-spectrin gene encoding the region of the alpha-spectrin chain surrounding the abnormal proteolytic cleavage site was normal. We identified a point mutation causing the replacement of a highly conserved leucine residue by proline at position 207 in the alpha-spectrin chain, a site 51 residues to the amino-terminal side of the abnormal proteolytic cleavage site. Analysis of the proposed triple helical model of spectrin repeats reveals that the mutation occurs in helix 2 at a position directly opposite the abnormal proteolytic cleavage site in helix 3, making this the first report of a mutation occurring in helix 2 of a repeat in the alpha I domain of spectrin. These results add to the molecular heterogeneity of mutations associated with HE/HPP and provide further support for the proposed triple helical model of spectrin. Disruption of this proposed alpha-helical structure by helix-breaking proline substitutions may result in a functionally defective spectrin chain.
Images
The Journal of Clinical Investigation