转自《国际糖尿病》研究人员：

梁华，张亚男，李麦心悦，严晋华，杨黛稚，骆斯慧，郑雪瑛，杨国庆，李卓，许雯，Leif Groop，翁建平

青少年发病的成人型糖尿病（MODY）是一种单基因疾病，具有常染色体显性遗传、早发病（<25岁）和非胰岛素依赖等特点，占糖尿病患者的1%～4%，至少13个不同基因（HNF4A、GCK、HNF1A、PDX1、HNF1B、NEUROD1、KLF11、CEL、PAX4、INS、BLK、ABCC8和KCNJ11）已被证明可导致MODY亚型1-13的发生。先前的研究表明，GCK基因（MODY2）、HNF1A（MODY3）和HNF4A（MODY1）基因的突变是西方人群中最常见的MODY病因，占所有MODY病例的80%～90%，但这些基因的突变仅能解释10%～20%亚洲（包括中国、日本和韩国）MODY的发病，亚洲MODY患者的主要遗传原因至今尚未查明。因此需要对MODY患病情况和突变谱进行研究。

由翁建平教授带领的研究团队，8月2日在线发表于J Diabetes Investig杂志的题为Recognition of Maturity-Onset Diabetes of the Young (MODY) in China的研究结果可谓代表我国特殊类型糖尿病最好的研究。现将讲究结果简述如下：

研究过程

患者和方法：

研究人员从35家医院招募了参加中华医学会糖尿病学分会（CDS）于2013~2016年发起的“单基因糖尿病国家登记项目”的76个无血缘关系的家庭，其中包括74个汉族家系，藏族和满族各1个。这些家庭均符合公认的MODY临床诊断标准：糖尿病家族史阳性，至少连续2代受影响；早发型高血糖症（至少1名家庭成员诊断年龄在25岁以下）；非胰岛素依赖性（不需要胰岛素治疗或即使在胰岛素治疗3年后血清C肽水平仍>0.60 ng/ml）。研究人员对这76个符合MODY临床诊断标准的无血缘关系家庭的先证者进行MODY候选基因或外显子靶向捕获测序，在GnomAD或ExAC数据库中，将MAF<0.01用于筛选显著变异，进行Sanger测序以验证发现，并通过SIFT、PolyPhen-2和PROVEAN或CADD对错义突变进行功能预测。

结果：

这76个家系，在31个家系中共检测到6个基因的32个突变，占MODY病例的40.79%。这些突变有之前报道过的，也有新发现的突变（包含了7个无义/移码突变和4个错义突变），均为可能致病性的突变，包括15个GCK突变（MODY2）、12个HNF1A突变（MODY3）、2个HNF4A突变（MODY1）、1个KLF11突变（MODY7）、1个PAX4突变（MODY9）和1个NEUROG3突变。除两个de novo突变（HNF4A-MODY1P.Cys808Ser和HNF1A-MODY3 p.Lys120Glu）外，所有突变均为遗传性改变。总的来说，MODY2突变家系占18.42%，HNF1A占15.79%，HNF4A占2.63%，PAX4、KLF11和NEUROG3各占1.32%。MODY2、MODY3/1和MODYX的临床特点与以往报道相似，NEUROG3 p.Arg55Glufs*23所致MODY的临床表型以高血糖和轻度间歇性腹痛为特征。

结论

本研究更新了MODY流行病学的新认识，即用已知致病基因解释MODY的比例高于先前报道，并发现NEUROG3可能是MODY的一个新的致病基因。具体讨论如下：

本研究的局限性如下：

（1）由于一些基因具有高度重复的复杂区域或假基因，故高通量测试无法达到100%的覆盖率，但总体覆盖率可以达到95%以上；

（2） MODY5是一种低外显率疾病，最常见的突变是全部或部分外显子的单等位基因缺陷。然而，我们的研究中使用的NGS不能检测到大基因组片段中的拷贝数变异（CNV）。多重连接依赖探针扩增（MLPA）是CNV检测的金标准，在MODY541的遗传诊断中被认为比比较基因组杂交阵列（aCGH）更有优势。因此，在没有MLPA分析的情况下估计MODY5患病率是我们研究的一个局限性。MODY5最常见的突变是17q12缺失，由于17 q12缺失引起的MODY5中70%是偶发的，本研究中使用的MODY筛查标准（如是否存在家族史）也可能影响MODY5患病率的评估。

最后，在我们的研究中，仍有60%的MODY患者没有确定的遗传原因，中国人群MODY的主要基因尚待鉴定。因此，需要对中国MODY患者进行更广泛的遗传学研究。

参考文献

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研究团队介绍

遗传因素和环境因素是糖尿病发生和发展的内因和外因，研究糖尿病（特别是其中的特殊类型糖尿病）的分子病因对于拓展我们对糖尿病发病分子缺陷机制的认识显得十分重要，而分子诊断又是指导遗传性疾病个体化治疗的前提和基础。翁建平教授及其团队自2001年开始建立糖尿病家系库，并开展特殊类型糖尿病的分子诊断技术，将基因诊断、分子遗传机制以及临床应用三方面相结合，指导临床个体化诊治。该研究团队开展了我国第一个胰岛素受体变异型糖尿病的研究，发现胰岛素受体B亚单位R1174W变异可导致糖尿病和低血糖；国内外首次报道葡萄糖激酶基因（GCK）E339K变异引起的青少年起病的成年型糖尿病（MODY）2型，并明确了此突变通过降低GCK 蛋白产量、酶催化活性、热稳定性和改变蛋白晶体构象，造成胰岛素分泌减少，进而发生糖尿病。这些研究结果回馈临床，直接指导临床治疗及预测疾病预后。2013年，翁建平教授牵头中华医学会糖尿病学分会发起的'单基因糖尿病全国登记项目'，对包括MODY、新生儿糖尿病、线粒体基因糖尿病、严重胰岛素抵抗综合征等疾病在内的130余家系进行了基因筛查，为这些单基因糖尿病提供了全国性数据资料，为后续科学研究奠定了基础。