A novel splicing mutation of ANK1 is associated with phenotypic heterogeneity of hereditary spherocytosis in a Chinese family
A novel splicing mutation of ANK1 is associated with phenotypic heterogeneity of hereditary spherocytosis in a Chinese family
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ANK1的一种新剪接突变与中国家族遗传性球形红细胞增多症的表型异质性相关
DOI：
10.1016/j.bbadis.2022.166595
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发表时间：
2022-11-08
影响因子：
6.2
通讯作者：
Shang，Xuan
中科院分区：
文献类型：
--
作者：
Xu，Linlin;Wei，Xiaofeng;Shang，Xuan
遗传性球形红细胞增多症（HS）是一种常见的血液遗传性疾病，可导致贫血、黄疸和脾肿大。它是由编码红细胞膜和骨骼蛋白的ANK 1、SPTA、SPTB、SLC 4A 1和EPB 42基因突变引起的。患者在表型和基因型方面表现出高度异质性，基因型-表型相关性仍需澄清。在此，通过全外显子组测序（WES）和桑格测序，在一个中国男孩中发现了一个新的剪接突变（ANK 1：c.4391-2 A>C），该男孩表现出中度严重的HS表型。然而，他的父亲表现出温和的表型，尽管携带相同的HS引起的突变。通过生物信息学和实验分析对ANK 1突变蛋白的功能进行了分析。与野生型ANK 1蛋白相比，突变蛋白（p.N1463Kfs*4）显示出不同的三维结构和改变的亚细胞定位。这些变化破坏了正常的细胞膜结构，并导致球形红细胞。从儿子和他的父亲的cDNA扩增揭示了差异的剪接突变产生的异常转录本的表达。我们认为，突变等位基因的低表达可能导致了父亲相对较轻的症状。我们的研究验证了ANK 1c。c.4391- 2A>C作为引起HS的新的致病性突变。我们还提供了新的见解解释家庭内的表型变异，这将大大提高临床诊断和遗传咨询的HS。
Hereditary spherocytosis (HS) is a common hematological genetic disorder that results in anemia, jaundice and splenomegaly. It is caused by mutations in the ANK1, SPTA, SPTB, SLC4A1 and EPB42 genes, which encode red blood cell membrane and skeletal proteins. Patients show high heterogeneity in phenotype and genotype and the genotype-phenotype correlation still requires clarification. Here, a novel splicing mutation (ANK1: c.4391-2 A>C) was identified by whole-exome sequencing (WES) and Sanger sequencing in a Chinese boy who exhibited a moderately severe HS phenotype. However, his father exhibited a mild phenotype, despite carrying the same HS-causing mutation. The function of the mutant ANK1 protein was analyzed by both bioinformatics and experimental analysis. The mutant protein (p.N1463Kfs*4) showed a different 3D-structure and altered subcellular localization, when compared with the wild-type ANK1 protein. These changes disrupted the normal cell membrane structure and resulted in spheroidized red blood cells. Amplification of cDNA from the son and his father revealed a difference in expression of the abnormal transcript produced by the splicing mutation. We proposed that the lower expression of the mutant allele may have contributed to the relatively mild symptoms of the father. Our study verified ANK1 c. c.4391-2 A>C as a novel pathogenic mutation that causes HS. We have also provided new insights into the interpretation of phenotypic variability within families, which could greatly improve the clinical diagnosis and genetic counseling of HS.