一个Ⅱ型先天性红细胞生成异常性贫血家系的僦3B基因型及表型分析  

Analysis of genotype and phenotype of SEC23B gene in a family affected with congenital dyserythropoietic anemia type Ⅱ

作　　者：李栋梁[1] 李博伦 瞿姗姗 曹玮 杨娅平 马印图[1] 侯天文[1] 

机构地区：[1]解放军白求恩国际和平医院,石家庄050082 [2]河北医科大学第三医院,石家庄050051 [3]承德医学院研究生院,河北067000

出　　处：《中华医学遗传学杂志》2017年第6期874-878,共5页Chinese Journal of Medical Genetics

摘　　要：目的对1个Ⅱ型先天性红细胞生成异常性贫血（congenital dyserythropojetic anemia，CDA）家系进行致病基因的突变及表型分析。方法应用目标序列捕获高通量二代测序技术对1例CDAⅡ型患者SEC23B基因的外显子及侧翼区进行测序，在确定先证者的致病基因型后，应用Sanger测序法进行验证，同时检测患者直系亲属的基因型，并用Mutation Taster与PolyPhen-2软件预测突变对蛋白功能的影响，用SWISS-MODEL软件对蛋白结构进行模拟分析。结果先证者SEC23B基因存在罕见的复合杂合错义突变C．1727T〉C（P．F576S）和C．1831C〉T（P．R611W），导致该基因的第576位氨基酸由苯丙氨酸变为丝氨酸，第611位由精氨酸变为色氨酸。Sanger测序证实了上述双重突变。先证者之姐检出C．1727T〉C杂合突变，父亲及儿子均检出C．1831C〉T杂合突变。此外，在先证者中检出一血色病相关基因HFE的杂合突变c．211C〉T（p．R71X），导致71位的精氨酸变为终止密码子，其父亲未检出此突变。上述3种突变的蛋白功能预测均为有害，分子模拟显示其改变了SEC23B蛋白的三维构象。先证者在脾脏切除后贫血有所好转，在祛铁治疗后铁蛋白有所下降。结论SEC23B基因c．1727T〉C与c．1831C〉T复合杂合突变很可能是该cDAⅡ型家系的分子发病原因，此基因型与临床表型密切相关。Objective To detect potential mutation in a family affected with congenital dyserythropoietic anemia type ]] （CDA ]] ）. Methods Targeted sequence capture and next-generation sequencing （NGS） were used to analyze the exons and exon-intron boundaries of the SEC23B gene in a clinically suspected CDA ]] patient. Genotypes of the relatives were validated by Sanger sequencing. Potential impact of amino acid substitution on the structure and function of SEC23B protein was predicted with MutationTaster and PolyPhen-2. The protein structure was predicted with SWISS-MODEL software. Results The proband was found to harbor double heterozygous mutations of the SEC23B gene, c. 1727T〉C （p. F576S） and c. 1831C〉T （p. R611W）, which resulted in amino acid substitutions p. F576S and p. R611W. Both mutations were confirmed by Sanger sequencing. The sister of the proband was found to have carried c. 1727T〉C （p. F576S）, while her father and son have carried c. 1831C〉T （p. R611W） mutation. In addition, the proband was detected to have carried c. 211C〉T （p. R71X） of the HFE gene, which resulted in substitution of arginine by a stop codon. The impact of above mutations on the structure or function of protein was predicted to be harmful. Splenectomy and iron chelation therapy have achieved effective improvement of anemia and iron overload. Computer simulation suggested that the mutations have altered the 3D structure of the SEC23B protein. Conclusion The novel compound mutations of c. 1727T〉C and c. 1831C〉T of the SEC23B gene probably underlie the CDA Ⅱ in the family, and there is a strong correlation between the genotype and phenotype.

关 键 词：SEC23B基因 突变 贫血 先天性红细胞生成异常性 目标序列捕获 二代测序 

分 类 号：R394[医药卫生—医学遗传学]