Møller A M, Dalgaard L T, Pociot F, Nerup J, Hansen T, Pedersen O
Steno Diabetes Center and Hagedorn Research Institute, Gentofte, Copenhagen, Denmark.
Diabetologia. 1998 Dec;41(12):1528-31. doi: 10.1007/s001250051101.
Mutations in the hepatocyte nuclear factor-1alpha (HNF-1alpha) gene are the cause of maturity-onset diabetes of the young type 3 (MODY3), which is characterised by a severe impairment of insulin secretion and an early onset of the disease. Also at onset of diabetes some MODY patients show similar clinical symptoms and signs as patients with Type I (insulin-dependent) diabetes mellitus. The objective of this study was to estimate the prevalence of MODY3 patients misclassified as Type I diabetic patients. From a large population-based sample of unrelated Danish Caucasian Type I diabetic patients with an affected first degree relative, 39 patients (6.7%) who did not carry any high-risk HLA-haplotypes, i.e. DR3 or DR4 or both were examined by single-strand conformational polymorphism scanning and direct sequencing of the coding region and the minimal promoter of the HNF-1alpha gene. Four of the 39 Type I diabetic patients (10%) were identified as carrying mutations in the HNF-1alpha gene. One patient carried a missense mutation (Glu48Lys) in exon 1, two patients carried a missense mutation (Cys241Gly) in exon 4 and one patient carried a frameshift mutation (Pro291fsdelA) in exon 4. The mutations were all identified in heterozygous form, segregated with diabetes, and were not identified in 84 unrelated, healthy subjects. Furthermore, family history in three of the four families showed diabetes in four consecutive generations, suggestive of an autosomal dominant inheritance. In conclusion, about 10% of Danish diabetic patients without a high-risk HLA-haplotype, originally classified as having Type I diabetes could have diabetes caused by mutations in the HNF-1alpha gene. Clinical awareness of family history of diabetes and mode of inheritance might help to identify and reclassify these diabetic subjects as MODY3 patients.
肝细胞核因子1α（HNF-1α）基因突变是青年发病的成年型糖尿病3型（MODY3）的病因，其特征是胰岛素分泌严重受损且疾病发病较早。在糖尿病发病时，一些MODY患者表现出与1型（胰岛素依赖型）糖尿病患者相似的临床症状和体征。本研究的目的是估计被误诊为1型糖尿病患者的MODY3患者的患病率。从大量基于人群的丹麦白种人1型糖尿病患者样本中选取了39名患者（6.7%），这些患者均有一名患病的一级亲属，且他们不携带任何高危HLA单倍型，即DR3或DR4或两者，对其进行单链构象多态性扫描以及HNF-1α基因编码区和最小启动子的直接测序。39名1型糖尿病患者中有4名（10%）被鉴定为携带HNF-1α基因突变。一名患者在第1外显子携带错义突变（Glu48Lys），两名患者在第4外显子携带错义突变（Cys241Gly），一名患者在第4外显子携带移码突变（Pro291fsdelA）。这些突变均以杂合形式被鉴定出来，与糖尿病共分离，且在84名无关的健康受试者中未被发现。此外，四个家族中有三个家族的家族史显示连续四代患有糖尿病，提示为常染色体显性遗传。总之，约10%原本被归类为1型糖尿病的丹麦糖尿病患者，若不携带高危HLA单倍型，其糖尿病可能由HNF-1α基因突变引起。对糖尿病家族史和遗传方式的临床认识可能有助于识别这些糖尿病患者并将其重新归类为MODY3患者。
