Positional cloning of "Lisch-Like", a candidate modifier of susceptibility to type 2 diabetes in mice.
Positional cloning of "Lisch-Like", a candidate modifier of susceptibility to type 2 diabetes in mice.
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DOI：
10.1371/journal.pgen.1000137
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发表时间：
2008-07-25
期刊：
影响因子：
4.5
通讯作者：
Leibel RL
中科院分区：
文献类型：
--
作者：
Dokmanovic-Chouinard M;Chung WK;Chevre JC;Watson E;Yonan J;Wiegand B;Bromberg Y;Wakae N;Wright CV;Overton J;Ghosh S;Sathe GM;Ammala CE;Brown KK;Ito R;LeDuc C;Solomon K;Fischer SG;Leibel RL
在404 Lepob/ob F2后代的C57 BL/6 J（B6）× DBA/2 J（DBA）的互交，我们映射了DBA相关的数量性状位点（QTL）远端Chr 1在169.6 Mb，集中在D1 Mit 110，糖尿病相关的表型，包括血糖，HbA 1c，胰岛组织学。在一系列也分离Lepob的B6.DBA同源/亚同源系中，该间隔被细化为1.8 Mb。B6.DBA同源小鼠的表型包括β细胞复制率降低，伴随β细胞质量降低、血液中胰岛素/葡萄糖比率降低、葡萄糖耐量降低和持续轻度低胰岛素血症性高血糖。在此间隔中的14个基因的核苷酸序列和表达分析鉴定了我们已指定为“Lisch样”（L1）作为最可能的候选者的预测基因。该基因在Chr1qH2.3上跨越62.7 kb，编码10个外显子，646个氨基酸的多肽，与Chr 7 qB 1上的Lsr和Chr 16 qB 3上的Ildr 1同源。预测Ll的最大同种型是具有免疫球蛋白样细胞外结构域和富含丝氨酸/苏氨酸的细胞内结构域的跨膜分子，所述细胞内结构域含有14-3-3结合结构域。L1的斑马鱼paradium的吗啉敲低导致肠区域内胚层发育的普遍延迟和胰岛素阳性细胞的分散。分离ENU诱导的L1无效等位基因的小鼠具有与B.D同源系相当的表型。人类直系同源物C1 orf 32位于Chr 1 q23 -25的30 Mb区域的中间，该区域反复与2型糖尿病相关。2型糖尿病（T2 D）占糖尿病病例的90%以上，是医学发病率和死亡率的主要原因。双胞胎研究表明，在肥胖症的背景下，多基因对易感性的贡献很大。虽然已经确定了大约10个对个体风险有重要贡献的基因，但很明显，其他基因仍有待确定。在这项研究中，我们将肥胖、耐糖尿病和易患糖尿病的小鼠品系杂交，以揭示小鼠Chr 1上与β细胞数量减少和血糖升高相关的遗传间隔。我们使用分子遗传学和计算方法缩小该区域以鉴定我们命名为“Lisch样”（L1）的新基因。T2 D中反复涉及到直系人类遗传间隔。具有降低Ll表达的诱导突变的小鼠在β细胞发育和葡萄糖代谢两者中受损，并且斑马鱼中同源基因的表达降低破坏胰岛发育。L1在T2 D的病理生理学中涉及的器官（下丘脑、胰岛、肝脏和骨骼肌）中表达，并且预测其编码可介导胆固醇转运和/或传递与细胞分裂相关的信号的跨膜蛋白。任何一种机制都可能介导对β细胞质量的影响，从而使T2 D易感。
In 404 Lepob/ob F2 progeny of a C57BL/6J (B6) x DBA/2J (DBA) intercross, we mapped a DBA-related quantitative trait locus (QTL) to distal Chr1 at 169.6 Mb, centered about D1Mit110, for diabetes-related phenotypes that included blood glucose, HbA1c, and pancreatic islet histology. The interval was refined to 1.8 Mb in a series of B6.DBA congenic/subcongenic lines also segregating for Lepob. The phenotypes of B6.DBA congenic mice include reduced β-cell replication rates accompanied by reduced β-cell mass, reduced insulin/glucose ratio in blood, reduced glucose tolerance, and persistent mild hypoinsulinemic hyperglycemia. Nucleotide sequence and expression analysis of 14 genes in this interval identified a predicted gene that we have designated “Lisch-like” (Ll) as the most likely candidate. The gene spans 62.7 kb on Chr1qH2.3, encoding a 10-exon, 646–amino acid polypeptide, homologous to Lsr on Chr7qB1 and to Ildr1 on Chr16qB3. The largest isoform of Ll is predicted to be a transmembrane molecule with an immunoglobulin-like extracellular domain and a serine/threonine-rich intracellular domain that contains a 14-3-3 binding domain. Morpholino knockdown of the zebrafish paralog of Ll resulted in a generalized delay in endodermal development in the gut region and dispersion of insulin-positive cells. Mice segregating for an ENU-induced null allele of Ll have phenotypes comparable to the B.D congenic lines. The human ortholog, C1orf32, is in the middle of a 30-Mb region of Chr1q23-25 that has been repeatedly associated with type 2 diabetes. Type 2 diabetes (T2D) accounts for over 90% of instances of diabetes and is a leading cause of medical morbidity and mortality. Twin studies indicate a strong polygenic contribution to susceptibility within the context of obesity. Although approximately ten genes making important contributions to individual risk have been identified, it is clear that others remain to be identified. In this study, we intercrossed obese, diabetes-resistant and diabetes-prone mouse strains to implicate a genetic interval on mouse Chr1 associated with reduced β-cell numbers and elevated blood glucose. We narrowed the region using molecular genetics and computational approaches to identify a novel gene we designated “Lisch-like” (Ll). The orthologous human genetic interval has been repeatedly implicated in T2D. Mice with an induced mutation that reduces Ll expression are impaired in both β-cell development and glucose metabolism, and reduced expression of the homologous gene in zebrafish disrupts islet development. Ll is expressed in organs implicated in the pathophysiology of T2D (hypothalamus, islets, liver, and skeletal muscle) and is predicted to encode a transmembrane protein that could mediate cholesterol transport and/or convey signals related to cell division. Either mechanism could mediate effects on β-cell mass that would predispose to T2D.
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