Glucokinase Gene Mutations: Structural and Genotype-Phenotype Analyses in MODY Children from South Italy
Glucokinase Gene Mutations: Structural and Genotype-Phenotype Analyses in MODY Children from South Italy
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DOI：
10.1371/journal.pone.0001870
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发表时间：
2008-04-02
期刊：
影响因子：
3.7
通讯作者：
Sacchetti, Lucia
中科院分区：
文献类型：
--
作者：
Tinto, Nadia;Zagari, Adriana;Sacchetti, Lucia
背景：成熟型2型糖尿病（或GCK MODY）是由葡萄糖激酶基因（GCK）突变引起的一种遗传性糖尿病。方法/主要发现：我们对来自意大利南部的30例疑似MODY患者进行了GCK基因直接测序筛选。通过分子模型分析突变诱导的蛋白结构改变。获得患者的生化、临床及记忆资料。30例患者中有16例（53%）检测到突变；鉴定出的12个突变中有9个是新突变（p.Glu70Asp, p.Phe123Leu, p.Asp132Asn, p.His137Asp, p.Gly162Asp, p.Thr168Ala, p.Arg392Ser, p.Glu290X, p.Gln106_Met107delinsLeu），并且位于催化所需的结构重排区域。突变位点在小结构域（7/12:59%）的发生率高于大结构域（4/12:33%）或连接区域（1/12:8%）。几乎所有患者均检测到轻度糖尿病表型[平均（SD） OGTT = 7.8 mMol/L(1.8)]，突变GCK患者的平均甘油三酯水平低于未突变GCK患者（p = 0.04）。结论：意大利南部地区GCK MODY患病率较高，GCK小结构域是MODY突变的热点。GCK突变的严重程度和遗传背景似乎在GCK MODY表型中起着相关的作用。确实，在相关患者（3对兄弟姐妹）中发现了部分基因型-表型相关性，但在两个具有相同突变的非亲属儿童中却没有。因此，分子方法允许医生确认诊断并预测突变的严重程度。
Background: Maturity onset diabetes of the young type 2 (or GCK MODY) is a genetic form of diabetes mellitus provoked by mutations in the glucokinase gene (GCK).Methodology/Principal Findings: We screened the GCK gene by direct sequencing in 30 patients from South Italy with suspected MODY. The mutation-induced structural alterations in the protein were analyzed by molecular modeling. The patients' biochemical, clinical and anamnestic data were obtained. Mutations were detected in 16/30 patients (53%); 9 of the 12 mutations identified were novel (p.Glu70Asp, p.Phe123Leu, p.Asp132Asn, p.His137Asp, p.Gly162Asp, p.Thr168Ala, p.Arg392Ser, p.Glu290X, p.Gln106_Met107delinsLeu) and are in regions involved in structural rearrangements required for catalysis. The prevalence of mutation sites was higher in the small domain (7/12: similar to 59%) than in the large (4/12: 33%) domain or in the connection (1/12: 8%) region of the protein. Mild diabetic phenotypes were detected in almost all patients [mean (SD) OGTT = 7.8 mMol/L (1.8)] and mean triglyceride levels were lower in mutated than in unmutated GCK patients (p = 0.04).Conclusions: The prevalence of GCK MODY is high in southern Italy, and the GCK small domain is a hot spot for MODY mutations. Both the severity of the GCK mutation and the genetic background seem to play a relevant role in the GCK MODY phenotype. Indeed, a partial genotype-phenotype correlation was identified in related patients (3 pairs of siblings) but not in two unrelated children bearing the same mutation. Thus, the molecular approach allows the physician to confirm the diagnosis and to predict severity of the mutation.