MOLECULAR HETEROGENEITY OF HEREDITARY PYROPOIKILOCYTOSIS - IDENTIFICATION OF A 2ND VARIANT OF THE SPECTRIN ALPHA-SUBUNIT

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  • 1 January 1983
    • journal article
    • research article
    • Vol. 62  (6) , 1182-1189
Abstract
In hereditary pyropoikilocytosis (HPP), the red cell membrane skeletons exhibit a mechanical instability that can be correlated to defective self-association of spectrin heterodimers. To determine the underlying molecular defect, HPP spectrin was subjected to limited tryptic digestion, followed by 1- and 2-dimensional separations of the peptides. Two of the HPP kindreds exhibited a marked decrease in 80,000-dalton peptide (previously identified as the spectrin dimer-dimer contact domain of the .alpha.-subunit) and a concomitant increase of the 74,000-dalton polypeptide (presumably derived from the 80,000-dalton domain) and a decrease in a 22,000-dalton polypeptide. Tryptic digests of 2 other HPP kindred that are characterized by a decrease or complete absence of the 80,000-dalton tryptic fragment are reported with a concomitant increase in fragments at 46,000 and 17,000 daltons. The 46,000-dalton fragment separated into multiple spots on isoelectric focusing, ranging in isoelectric point from 5.25 to 5.35, and the 17,000-dalton fragment focused to a single spot at 5.4. Minor fragments at 56,000 and 22,000 daltons were also decreased, while a 38,000-dalton fragment increased. Limited tryptic digestion of the separated .alpha.- and .beta.-subunits revealed that the 74,000-dalton fragment in the first group of patients and the 46,000-dalton fragment in the 2nd group of patients were derived from the .alpha.-subunit. Both subtypes exhibited a similar defect of spectrin self-association, with 30%-38% of spectrin dimers in 0.degree. C extracts. At least 2 distinct forms of structurally defective spectrin may give rise to the clinical presentation of HPP.