Seven mutations in the human insulin gene linked to permanent neonatal/infancy-onset diabetes mellitus
Seven mutations in the human insulin gene linked to permanent neonatal/infancy-onset diabetes mellitus
复制标题
人类胰岛素基因的七种突变与永久性新生儿/婴幼儿糖尿病有关
DOI：
10.1172/jci33777
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发表时间：
2008-06-01
影响因子：
15.9
通讯作者：
Barbetti, Fabrizio
中科院分区：
文献类型：
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作者：
Colombo, Carlo;Porzio, Ottavia;Barbetti, Fabrizio
永久性新生儿糖尿病（PNDM）是一种罕见的疾病，通常在出生后6个月内出现。虽然有几个基因与这种疾病有关，但在意大利记录的几乎一半病例中，遗传原因仍然未知。由于携带Ins 2基因突变的秋田小鼠表现出与胰腺β细胞凋亡相关的PNDM，我们对具有未鉴定突变的PNDM受试者的人胰岛素基因进行了测序。我们在10个无关的先证者中发现了7个杂合突变。在这些患者中的8例中，在糖尿病发作时可检测到胰岛素分泌，但随着时间的推移迅速下降。当这些突变胰岛素原在HEK 293细胞中表达时，我们观察到胰岛素蛋白折叠和分泌的缺陷。在这些实验中，突变胰岛素原的表达也与Grp 78蛋白表达和XBP 1 mRNA剪接（内质网应激的2种标志物）增加以及细胞凋亡增加相关。与表达WT胰岛素原的细胞相比，类似转染的INS-1 E胰岛素瘤细胞的活力降低。总之，我们发现胰岛素基因突变促进胰岛素原错误折叠可能导致PNDM。
Permanent neonatal diabetes mellitus (PNDM) is a rare disorder usually presenting within 6 months of birth. Although several genes have been linked to this disorder, in almost half the cases documented in Italy, the genetic cause remains unknown. Because the Akita mouse bearing a mutation in the Ins2 gene exhibits PNDM associated with pancreatic beta cell apoptosis, we sequenced the human insulin gene in PNDM subjects with unidentified mutations. We discovered 7 heterozygous mutations in 10 unrelated probands. In 8 of these patients, insulin secretion was detectable at diabetes onset, but rapidly declined over time. When these mutant proinsulins were expressed in HEK293 cells, we observed defects in insulin protein folding and secretion. In these experiments, expression of the mutant proinsulins was also associated with increased Grp78 protein expression and XBP1 mRNA splicing, 2 markers of endoplasmic reticulum stress, and with increased apoptosis. Similarly transfected INS-1E insulinoma cells had diminished viability compared with those expressing WT proinsulin. In conclusion, we find that mutations in the insulin gene that promote proinsulin misfolding may cause PNDM.