Wolford J K, Bogardus C, Prochazka M
Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, Phoenix, Arizona, 85016,
Mol Genet Metab. 1999 Jan;66(1):62-7. doi: 10.1006/mgme.1998.2775.
The expansion of polymorphic CAG/CTG repeats in specific genes causes several neurodegenerative disorders and in many instances the length of the disease-causing repeat correlates with the onset age and/or severity of symptoms. Type 2 diabetes mellitus has features in common with diseases resulting from trinucleotide repeat expansion, including a variable age of disease onset and penetrance. We have investigated whether CAG/CTG repeat expansion contributes to the genetic etiology of type 2 diabetes in the Pima Indians, a population with the highest reported prevalence of this disease. Using the Repeat Expansion Detection (RED) method, we determined the size range in nondiabetic Pimas to be between (CAG)20 and (CAG)130 (mean repeat length = 195 bp), which is significantly larger than the mean size reported in Caucasians (150 bp). We compared the distribution of CAG/CTG repeat lengths among 40 Pimas with an early onset of type 2 diabetes (<22 years) and 38 nondiabetic subjects (>55 years). A 240-bp CAG/CTG RED product was found more frequently in early onset diabetics relative to nondiabetic controls (26% vs 11%), whereas a 210-bp band was more prominent in unaffected subjects (29% vs 13%); however, these differences were not statistically significant. In one Pima kindred, we also identified large RED products (>/=360 bp) that displayed intergenerational instability among family members. However, these expansions were not associated with diabetes or any other clinical abnormalities in the carriers. We conclude that this unstable CAG/CTG repeat may represent a novel locus, consisting of large, but apparently nonpathogenic, unstable sequences.
特定基因中多态性CAG/CTG重复序列的扩增会导致多种神经退行性疾病，而且在许多情况下，致病重复序列的长度与发病年龄和/或症状严重程度相关。2型糖尿病具有与三核苷酸重复序列扩增所致疾病相同的特征，包括发病年龄和外显率的差异。我们研究了CAG/CTG重复序列扩增是否在皮马印第安人中2型糖尿病的遗传病因中起作用，该人群是报道中该病患病率最高的群体。使用重复序列扩增检测（RED）方法，我们确定非糖尿病皮马人的重复序列大小范围在（CAG）20至（CAG）130之间（平均重复长度 = 195 bp），这显著大于高加索人报道的平均大小（150 bp）。我们比较了40例2型糖尿病早发患者（<22岁）和38例非糖尿病受试者（>55岁）中CAG/CTG重复序列长度的分布。相对于非糖尿病对照组，240 bp的CAG/CTG RED产物在糖尿病早发患者中更常见（26%对11%），而210 bp的条带在未受影响的受试者中更突出（29%对13%）；然而，这些差异无统计学意义。在一个皮马家族中，我们还鉴定出大的RED产物（≥360 bp），其在家庭成员之间表现出代际不稳定性。然而，这些扩增与携带者的糖尿病或任何其他临床异常无关。我们得出结论，这种不稳定的CAG/CTG重复序列可能代表一个新的基因座，由大的但显然无致病性的不稳定序列组成。
