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 PROTEOLYTIC CLEAVAGE SITE - EVIDENCE FOR THE FUNCTIONAL IMPORTANCE OF THE TRIPLE HELICAL MODEL OF SPECTRIN

被引:42
作者
GALLAGHER, PG
TSE, WT
COETZER, T
LECOMTE, MC
GARBARZ, M
ZARKOWSKY, HS
BARUCHEL, A
BALLAS, SK
DHERMY, D
PALEK, J
FORGET, BG
机构
[1] YALE UNIV, SCH MED, DEPT PEDIAT HUMAN GENET & INTERNAL MED, NEW HAVEN, CT 06510 USA
[2] TUFTS UNIV, ST ELIZABETHS HOSP, SCH MED, DEPT BIOMED RES, BOSTON, MA 02135 USA
[3] HOP BEAUJON, INSERM, U160, F-92118 CLICHY, FRANCE
[4] WASHINGTON UNIV, SCH MED, DEPT PEDIAT, ST LOUIS, MO 63110 USA
[5] HOP ST LOUIS, F-75010 PARIS, FRANCE
[6] THOMAS JEFFERSON UNIV, CARDEZA FDN HEMATOL RES, DEPT MED, PHILADELPHIA, PA 19107 USA
[7] UNIV WITWATERSRAND, S AFRICAN INST MED RES, DEPT HAEMATOL, JOHANNESBURG 2193, SOUTH AFRICA
关键词
DNA SEQUENCE; ERYTHROCYTE MEMBRANE SKELETON; HEMOLYTIC ANEMIA; POLYMERASE CHAIN REACTION;
D O I
10.1172/JCI115669
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
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.
引用
收藏
页码:892 / 898
页数:7
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