Mutation of a highly conserved isoleucine disrupts hydrophobic interactions in the αβ spectrin self-association binding site

• Published in: Laboratory investigation 2004-02, Vol.84 (2), p.229-234
• Main Authors: Gallagher, Patrick G, Zhang, Zhushan, Morrow, Jon S, Forget, Bernard G
• Format: Article
• Language: English
• Subjects: Biological and medical sciences; Biotechnology; dynamic molecular modeling; elliptocytosis; Fundamental and applied biological sciences. Psychology; Investigative techniques, diagnostic techniques (general aspects); Laboratory Medicine; Medical sciences; Medicine; Medicine & Public Health; mutation; Pathology; pyropoikilocytosis; research-article; spectrin
• ISSN: 0023-6837; 1530-0307
• DOI: 10.1038/labinvest.3700029

We studied an infant with severe neonatal hemolytic anemia and hyperbilirubinemia that evolved into a partially compensated ellipto-poikilocytic anemia. His father had typical elliptocytosis. Their erythrocyte membranes demonstrated structural and functional defects in spectrin. Genetic studies revealed that the proband and his father were heterozygous for an α-spectrin mutation, Ile24Thr, in the αβ spectrin self-association binding site. The proband also carried the low expression allele αLELYin trans, influencing the clinical phenotype. The importance of isoleucine in this position of the proposed triple helical model of spectrin repeats is highlighted by its evolutionary conservation in all α spectrins from Drosophila to humans. Molecular modeling demonstrated that replacement of a hydrophobic isoleucine with a hydrophilic threonine disrupts highly conserved hydrophobic interactions in the interior of the spectrin triple helix critical for spectrin function.