颅锁骨发育不良的三个RUNX2基因新突变  

Identification of three novel frameshift mutations in the RUNX2 gene in three sporadic Chinese cases with cleidocranial dysplasia

作　　者：齐展[1] 杨威[1] 孟岩[1] 刘雅萍[1] 

机构地区：[1]中国医学科学院基础医学研究所医学遗传学系,北京100005

出　　处：《中华医学遗传学杂志》2014年第4期415-419,共5页Chinese Journal of Medical Genetics

基　　金：2010-2013教育部“长江学者和创新团队发展计划”（LRT1006）

摘　　要：目的通过对3例散发的颅锁骨发育不良患者进行RUNX2基因编码区的扩增及测序，寻找RUNX2基因突变，为家系进行遗传咨询和产前诊断提供依据。方法抽取患者及其父母外周血，提取基因组DNA，PcR扩增RUNx2基因的7个编码外显子并测序；并对患者突变所在外显子的PCR产物经T-A克隆后再次测序。结果例1的RUNX2第1外显子发生了1个80bp的c．227_306del杂合性缺失突变，引起读码框移位并提前出现终止密码（p．Ala76GlyfsX58）；例2的RUNX2第2外显子发生了1个c.471_472dupGG杂合重复突变，亦导致读码框改变及提前出现终止密码（p．Alal58Glyfsx19）；例3的RUNX2第17显子发生了1个c．1321dupT杂合重复突变，同样导致读码框改变和提前出现终止密码（p．Ser370Phefsxl3）。这三个移码突变经查询HGMD突变数据库及国内外文献均未见报道。结论发现了3种新的导致颅锁骨发育不良的RUNX2基因突变，新的突变扩展了RUNX2基因的突变谱，可为这些家系提供准确可靠的遗传咨询和产前诊断。Objective To investigate the molecular etiology of three patients with sporadic cleidocranial dysplasia （CCD） and to provide genetic counseling and prenatal diagnosis for the family members based on the identified mutations. Methods Genomic DNA was extracted from peripheral blood samples using a standard method. All 7 coding exons of the RUNX2 gene and their flanking intronic sequences were amplified by PCR and sequenced directly. The PCR products of the exons with mutations from the three patients were cloned into a T-vector. Positive clones were sequenced. Results The three patients who have the typical CCD phenotypes involving clavicles, calvarium, stature, and teeth have carried various frameshift mutations in the RUNX2 gene. Patient 1 has a gross deletion of 80 nucleotides in exon 1 （c. 227 306del）, which caused a frameshift beginning at the Q/A repeat of the polypeptide and a premature termination （p. Ala76GlyfsX58）. Patient 2 has a 2-bp duplication in exon 2 （c. 471_472dupGG）, which also caused a frameshift and a premature termination （p. Ala158GlyfsX19）. Patient 3 has a T duplication in exon 7 （c. 1321dupT）, which caused a frameshift and a premature termination （p. Ser370PhefsX13） as well. Conclusion The three novel mutations in RUNX2 are the underlying molecular mechanism for the CCD phenotypes of three sporadic Chinese patients, respectively. These have broadened the mutation spectrum of RUNX2 gene and provided a molecular basis for the genetic counseling and prenatal diagnosis for the affected families.

关 键 词：颅锁骨发育不良 RUNX2基因 缺失突变 重复突变 

分 类 号：R596.1[医药卫生—内科学]