儿童Peutz—Jeghers综合征一例家系临床特征及LKB1基因突变分析

Clinical characteristics and mutation analysis of the LKB1 gene in a Peutz-Jeghers syndrome petfigree

目的研究一例儿童Peutz—Jeghers综合征家系的临床特征及其LKBl基因突变。方法收集家系的临床资料，并分别留取家系成员外周血，采用多重连接探针扩增技术、DNA测序分别检测LKBl基因大片段缺失、碱基突变、碱基插入和缺失，同时采用PCR结合变性高效液相色谱筛查验证突变位点在正常人群中的分布。生物信息学分析突变位点对编码蛋白质结构和功能的影响。结果先证者具有典型的皮肤黏膜黑斑、多发胃肠道错构瘤性息肉，先证者及1名家系成员均携带LKBl基因c．924G〉C位点的病理性胚系突变，导致Trp308Cys的错义突变的发生；这一突变在正常人群中不存在；蛋白质结构和功能分析结果显示Trp308Cys突变可改变蛋白质的空间构象，进而影响了蛋白质功能。结论Peutz—Jeghers综合征具有皮肤黏膜色素沉着、胃肠道多发性错构瘤性息肉和家族遗传性三大特征，呈常染色体显性遗传，LKBl基因胚系突变是其致病因素，利用LKB1基因鉴定和突变筛选所有患者及一级亲属对明确诊断及改善其家族的生存期具有重要意义。

Objective To investigate clinical characteristics and mutation of the LKB1 gene in a Peutz-Jeghers syndrome （PJS） pedigree. Method Clinical data of a PJS family were analyzed and LKB1 gene mutation was detected by systematic screening with multiplex ligation-dependent probe amplification （MLPA） and DNA sequencing. Meanwhile, two hundred and fifty healthy adults were enrolled in this study and denaturing high performance liquid chromatography （PCR-DHPLC） was carried out to verify the mutation excluding polymorphism sites found in this family. Changes in protein structure and function caused by the mutated coding sequence was analyzed by SWISS-MODEL software. Result The proband had pigmented mucocutaneous lesions and multiple hamartomatous polyps in the gastrointestinal tract. There was no fragment deletion of LKB1 gene detected by MLPA. Among PJS family and 250 healthy adults, germline mutation c. 924G 〉 C of LKB1 which cause Trp308Cys in protein sequence was identified only in the proband and another affected member. LKB1 protein activity could be reduced due to changes in LKB1 protein conformation structure by Trp308Cys. Conclusion Peutz-Jeghers syndrome （PJS） is an autosomal dominant disorder characterised by mucocutaneous pigmentation, multiple gastrointestinal hamartomatous polyps and heredofamilial nature. Gene identification and mutagen screening of LKB1 gene in all PJS patients and first degree relatives will contribute to a definite diagnosis and improve the life span of the family.