Desbois-Mouthon C, Magré J, Amselem S, Reynet C, Blivet M J, Goossens M, Capeau J, Besmond C
Institut National de la Santé et de la Recherche Médicale (INSERM U-402), Paris, France.
J Clin Endocrinol Metab. 1995 Jan;80(1):314-9. doi: 10.1210/jcem.80.1.7829633.
Lipoatrophic diabetes (LD) is a syndrome with congenital or delayed onset, characterized by severe insulin resistance and generalized lipoatrophy. Using denaturing gradient gel electrophoresis and sequencing, we have investigated the contribution of defects in the insulin receptor (IR) gene in LD. First, we performed an association study between the IR gene and congenital lipoatrophy in two families with consanguineous parents and one or two affected children (patients D1, D2, and D3). Segregation analysis of intragenic polymorphisms excluded a linkage between the IR locus and the LD phenotype in both families. Second, we screened for mutations in all exons and splice site junctions of the IR gene from patients D1-D3 and 11 additional unrelated patients with congenital or delayed forms of LD. The IR sequence proved to be normal in all 14 subjects because nucleotide variations that we detected were silent. The relative levels of expression of the 2 alleles of the IR gene were evaluated by allele-specific oligonucleotide hybridization in cells from most of these patients, and no gross alteration was detected. Overall, these results provide the first clear evidence against the involvement of the IR gene in the pathogenesis of any clinical form of LD.
脂肪萎缩性糖尿病（LD）是一种先天性或迟发性综合征，其特征为严重胰岛素抵抗和全身性脂肪萎缩。我们使用变性梯度凝胶电泳和测序技术，研究了胰岛素受体（IR）基因缺陷在LD发病机制中的作用。首先，我们在两个父母近亲结婚且有一到两个患病子女（患者D1、D2和D3）的家庭中，进行了IR基因与先天性脂肪萎缩的关联研究。对基因内多态性的分离分析排除了两个家庭中IR基因座与LD表型之间的连锁关系。其次，我们对患者D1 - D3以及另外11名患有先天性或迟发性LD的无关患者的IR基因所有外显子和剪接位点连接区进行了突变筛查。在所有14名受试者中，IR序列均正常，因为我们检测到的核苷酸变异均为沉默变异。我们通过等位基因特异性寡核苷酸杂交技术，对这些患者大多数细胞中IR基因两个等位基因的相对表达水平进行了评估，未检测到明显改变。总体而言，这些结果首次明确证明IR基因不参与任何临床类型LD的发病机制。
