Gallagher P G, Petruzzi M J, Weed S A, Zhang Z, Marchesi S L, Mohandas N, Morrow J S, Forget B G
Department of Pediatrics, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
J Clin Invest. 1997 Jan 15;99(2):267-77. doi: 10.1172/JCI119155.
We studied an infant with severe nonimmune hemolytic anemia and hydrops fetalis at birth. His neonatal course was marked by ongoing hemolysis of undetermined etiology requiring repeated erythrocyte transfusions. He has remained transfusion-dependent for more than 2 yr. A previous sibling born with hemolytic anemia and hydrops fetalis died on the second day of life. Peripheral blood smears from the parents revealed rare elliptocytes. Examination of their erythrocyte membranes revealed abnormal mechanical stability as well as structural and functional abnormalities in spectrin. Genetic studies revealed that the proband and his deceased sister were homozygous for a mutation of betaIsigma1 spectrin, L2025R, in a region of spectrin that is critical for normal function. The importance of leucine in this position of the proposed triple helical model of spectrin repeats is highlighted by its evolutionary conservation in all beta spectrins from Drosophila to humans. Molecular modeling demonstrated the disruption of hydrophobic interactions in the interior of the triple helix critical for spectrin function caused by the replacement of the hydrophobic, uncharged leucine by a hydrophilic, positively charged arginine. This mutation must also be expressed in the betaIsigma2 spectrin found in muscle, yet pathologic and immunohistochemical examination of skeletal muscle from the deceased sibling was unremarkable.
我们研究了一名出生时患有严重非免疫性溶血性贫血和胎儿水肿的婴儿。他的新生儿期以病因不明的持续溶血为特征，需要反复进行红细胞输血。他在两年多的时间里一直依赖输血。之前一名患有溶血性贫血和胎儿水肿的同胞在出生第二天死亡。父母的外周血涂片显示有罕见的椭圆形红细胞。对他们红细胞膜的检查发现机械稳定性异常以及血影蛋白的结构和功能异常。基因研究表明，先证者及其已故的姐姐在血影蛋白对正常功能至关重要的区域存在βIsigma1血影蛋白L2025R突变的纯合子。从果蝇到人类的所有β血影蛋白中亮氨酸在血影蛋白重复序列的拟三螺旋模型的这个位置上的进化保守性突出了其重要性。分子建模表明，由于亲水性带正电荷的精氨酸取代了疏水性不带电荷的亮氨酸，导致三螺旋内部对血影蛋白功能至关重要的疏水相互作用受到破坏。这种突变也必须在肌肉中发现的βIsigma2血影蛋白中表达，但对已故同胞的骨骼肌进行病理和免疫组化检查未发现异常。
