Mutations in GCK and HNF-1α explain the majority of cases with clinical diagnosis of MODY in Spain
Mutations in GCK and HNF-1α explain the majority of cases with clinical diagnosis of MODY in Spain
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DOI：
10.1111/j.1365-2265.2007.02921.x
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发表时间：
2007-10-01
影响因子：
3.2
通讯作者：
Castano, Luis
中科院分区：
文献类型：
--
作者：
Estalella, Itziar;Rica, Itxaso;Castano, Luis
目的对MODY患者进行分组方法对GCK（MODY2）、HNF-1 α（MODY3）、HNF-1 α（MODY4）、HNF-1 α（MODY5）、HNF-1 α（MODY6）、HNF-1 α（MODY7）、HNF-1 α（MODY8）、HNF-1 α（MODY9通过DNA测序对95名临床诊断为MODY的无关指数先证者（47名男性/48名女性;平均年龄9.9 ± 5.2岁）进行HNF-4 α（MODY 1）和HNF-1 β（MODY 5）基因测定。结果76个家系存在GCK突变（其中34个未报道），8个家系存在HNF-1 α突变，1个家系存在HNF-1 β基因组重排。未发现HNF-4 α的改变。因此，研究组中的相对频率为80%MODY2，8.5%MODY3和1%MODY5。根据遗传状态比较MODY 2和MODY 3患者的临床参数，在诊断时的年龄方面存在显著差异（9.4 +/- 5.4年vs. 12.7 +/- 4.6年），诊断（葡萄糖耐量受损vs.糖尿病），使用诊断试验（OGTT与空腹血糖），治疗（饮食和运动vs.胰岛素/口服降糖药）和出生体重结论本组病例中90%以上的MODY是由GCK（MODY 2）和HNF-1 α（MODY 3）基因突变引起的，尽管每种形式的相对流行率的差异可能部分是由于患者转诊偏倚（儿科vs.成人）。一般来说，MODY 2患者的诊断年龄比MODY 3患者更早，糖尿病的形式也更温和。此外，大多数MODY 2突变患者接受饮食治疗，而半数MODY 3患者接受药物治疗。
Objective The aim of this study was to group patients with MODY (maturity-onset diabetes of the young) according to the genetic alterations underlying the disease and to investigate their clinical characteristics.Patients and methods Molecular analysis of GCK (MODY2), HNF-1 alpha (MODY3), HNF-4 alpha (MODY1) and HNF-1 beta (MODY5) genes was performed by DNA sequencing in 95 unrelated index probands (47M/48F; mean age 9.9 +/- 5.2 years) with clinical diagnosis of MODY. After classification into MODY subtypes according to the genetic alterations, clinical characteristics were compared between the groups.Results Seventy-six families were shown to carry mutations in GCK (34 of them previously unreported), eight families presented HNF-1 alpha mutations, and a large genomic rearrangement in HNF-1 beta was found in a family. No alteration was found in HNF-4 alpha. Thus, relative frequencies in the group studied were 80% MODY2, 8.5% MODY3 and 1% MODY5. Comparison of clinical parameters according to genetic status showed significant differences between MODY2 and MODY3 patients in age at diagnosis (9.4 +/- 5.4 years vs. 12.7 +/- 4.6 years), diagnosis (impaired glucose tolerance vs. diabetes), diagnostic test used (OGTT vs. fasting glucose), treatment (diet and exercise vs. insulin/oral antidiabetic agents) and birth weight (2.96 +/- 0.44 kg vs. 3.40 +/- 0.67 kg).Conclusion Almost 90% of the MODY cases in the group studied are explained by mutations in the major genes GCK (MODY2) and HNF-1 alpha (MODY3), although differences in the relative prevalence of each form could be partly due to patient referral bias (paediatric vs. adult). In general, patients with MODY2 were diagnosed at an earlier age in life than MODY3 patients and had a milder form of diabetes. Moreover, the majority of patients with MODY2 mutations were treated with diet whereas half of MODY3 patients received pharmacological treatment.