Characterization of the underlying molecular defect in hereditary spherocytosis associated with spectrin deficiency.
Characterization of the underlying molecular defect in hereditary spherocytosis associated with spectrin deficiency.
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DOI：
10.1182/blood.v90.1.398.398_398_406
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发表时间：
1997-07
期刊：
影响因子：
20.3
通讯作者：
Hani Hassoun;J. Vassiliadis;J. Murray;P. Njølstad;J. J. Rogus-J.;S. Ballas;F. Schaffer;Petr Jarolim;V. Brabec;Jiri Palek
中科院分区：
文献类型：
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作者：
Hani Hassoun;J. Vassiliadis;J. Murray;P. Njølstad;J. J. Rogus-J.;S. Ballas;F. Schaffer;Petr Jarolim;V. Brabec;Jiri Palek
根据涉及血影蛋白、锚蛋白、带 3 和蛋白 4.2 的特定红细胞膜蛋白缺陷，定义了几类遗传性球形红细胞增多症 (HS) 患者。目前正在发现编码这些蛋白质的基因的突变。关于血影蛋白，最近仅报道了三例与 HS 和血影蛋白缺乏相关的 β-血影蛋白基因突变的孤立病例。我们使用 SSCP 技术在 40 个患有与血影蛋白缺陷或血影蛋白和锚蛋白联合缺陷相关的 HS 家族中筛选了 β-血影蛋白基因的编码区。在本报告中，我们描述了 11 个不相关家族中 β-血影蛋白基因的 6 种移码和无义突变以及 4 种错义突变。利用突变引入的限制性内切酶识别序列的修饰，我们表明，在所有移码和无义突变的情况下，与基因组DNA相比，cDNA水平的杂合性丢失，反映了突变体mRNA转录本的缺失。在一个拥有 6 代、112 名成员的庞大谱系的家族中，我们牢固地确立了一种 β-血影蛋白无效突变的常染色体显性遗传。所描述的大多数突变导致轻度至中度常染色体显性 HS 的表型，与明显的球形红细胞增多症和频繁的刺状细胞（8% 至 15% 棘细胞）相关。一种错义突变似乎与该疾病的隐性形式有关。还描述了 β-血影蛋白基因编码区的五种常见限制性酶多态性。总体而言，这些发现强调了 β-血影蛋白基因突变在 HS 发病机制中的重要性，并再次强调了这种疾病潜在分子基础的极端异质性。
Several subsets of patients with hereditary spherocytosis (HS) have been defined based on the specific red blood cell membrane protein deficiencies involving spectrin, ankyrin, band 3, and protein 4.2. Mutations of the genes encoding these proteins are currently being uncovered. Regarding spectrin, only three isolated cases of beta-spectrin gene mutations were recently reported in association with HS and spectrin deficiency. We have screened the coding region of the beta-spectrin gene using the SSCP technique, in 40 families with HS associated with spectrin deficiency or combined spectrin and ankyrin deficiencies. In this report we describe six frameshift and nonsense mutations and four missense mutations of the beta-spectrin gene in 11 unrelated families. Taking advantage of modifications in the restriction enzyme recognition sequences introduced by the mutations, we show, in all cases of frameshift and nonsense mutations, the loss of heterozygosity at the cDNA level when compared to genomic DNA, reflecting the absence of the mutant mRNA transcripts. In one family with a large pedigree including six generations and 112 members, we firmly establish the autosomal dominant inheritance of one of the beta-spectrin null mutations. Most of the mutations described are responsible for a phenotype of mild to moderate autosomal dominant form of HS associated with a conspicuous spherocytosis with frequent spiculated cells (8% to 15% acanthocytes). One missense mutation appears to be associated with a recessive form of the disease. Five common restriction enzyme polymorphisms of the coding region of the beta-spectrin gene are also described. Overall, these findings underscore the importance of the beta-spectrin gene mutations in the pathogenesis of HS and reemphasizes the extreme heterogeneity of the underlying molecular basis of this condition.