Clee Susanne M, Yandell Brian S, Schueler Kathryn M, Rabaglia Mary E, Richards Oliver C, Raines Summer M, Kabara Edward A, Klass Daniel M, Mui Eric T-K, Stapleton Donald S, Gray-Keller Mark P, Young Matthew B, Stoehr Jonathan P, Lan Hong, Boronenkov Igor, Raess Philipp W, Flowers Matthew T, Attie Alan D
Department of Biochemistry, University of Wisconsin-Madison, Madison, Wisconsin 53706, USA.
Nat Genet. 2006 Jun;38(6):688-93. doi: 10.1038/ng1796. Epub 2006 May 7.
We previously mapped the type 2 diabetes mellitus-2 locus (T2dm2), which affects fasting insulin levels, to distal chromosome 19 in a leptin-deficient obese F2 intercross derived from C57BL/6 (B6) and BTBR T+ tf/J (BTBR) mice. Introgression of a 7-Mb segment of the B6 chromosome 19 into the BTBR background (strain 1339A) replicated the reduced insulin linked to T2dm2. The 1339A mice have markedly impaired insulin secretion in vivo and disrupted islet morphology. We used subcongenic strains derived from 1339A to localize the T2dm2 quantitative trait locus (QTL) to a 242-kb segment comprising the promoter, first exon and most of the first intron of the Sorcs1 gene. This was the only gene in the 1339A strain for which we detected amino acid substitutions and expression level differences between mice carrying B6 and BTBR alleles of this insert, thereby identifying variation within the Sorcs1 gene as underlying the phenotype associated with the T2dm2 locus. SorCS1 binds platelet-derived growth factor, a growth factor crucial for pericyte recruitment to the microvasculature, and may thus have a role in expanding or maintaining the islet vasculature. Our identification of the Sorcs1 gene provides insight into the pathway underlying the pathophysiology of obesity-induced type 2 diabetes mellitus.
我们先前将影响空腹胰岛素水平的2型糖尿病-2基因座（T2dm2）定位到19号染色体远端，该定位是在源自C57BL/6（B6）和BTBR T+ tf/J（BTBR）小鼠的瘦素缺乏型肥胖F2杂交群体中进行的。将B6 19号染色体上一个7兆碱基的片段导入BTBR背景（1339A品系），重现了与T2dm2相关的胰岛素降低现象。1339A小鼠在体内胰岛素分泌明显受损，胰岛形态也遭到破坏。我们利用源自1339A的亚同源近交系将T2dm2数量性状基因座（QTL）定位到一个242千碱基的片段，该片段包含Sorcs1基因的启动子、首个外显子和大部分首个内含子。这是1339A品系中唯一的一个基因，我们在携带该插入片段B6和BTBR等位基因的小鼠之间检测到了氨基酸替换和表达水平差异，从而确定Sorcs1基因内的变异是与T2dm2基因座相关表型的基础。SorCS1结合血小板衍生生长因子，这是一种对周细胞募集到微血管至关重要的生长因子，因此可能在扩展或维持胰岛脉管系统中发挥作用。我们对Sorcs1基因的鉴定为肥胖诱导的2型糖尿病病理生理学的潜在通路提供了深入了解。
