The proprotein convertase subtilisin/Kexin type 1 (PCSK1/PC1) protein processes inactive pro-hormone precursors into biologically active hormones in a number of neuroendocrine and endocrine cell types. Patients with recessive mutations in PCSK1 exhibit a complex spectrum of traits including obesity, diarrhoea and endocrine disorders. We describe here a new mouse model with a point mutation in the Pcsk1 gene that exhibits obesity, hyperphagia, transient diarrhoea and hyperproinsulinaemia, phenotypes consistent with human patient traits. The mutation results in a pV96L amino acid substitution and changes the first nucleotide of mouse exon 3 leading to skipping of that exon and in homozygotes very little full-length transcript. Overexpression of the exon 3 deleted protein or the 96L protein results in ER retention in Neuro2a cells. This is the second Pcsk1 mouse model to display obesity phenotypes, contrasting knockout mouse alleles. This model will be useful in investigating the basis of endocrine disease resulting from prohormone processing defects.

中文翻译：

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小鼠Pcsk1基因中的一种新型突变，显示出肥胖和糖尿病。

在许多神经内分泌和内分泌细胞类型中，前蛋白转化酶枯草杆菌蛋白酶/ Kexin 1型（PCSK1 / PC1）蛋白将无活性的激素前体加工成具有生物活性的激素。PCSK1隐性突变的患者表现出复杂的性状，包括肥胖，腹泻和内分泌失调。我们在这里描述一种新的小鼠模型，该模型在Pcsk1基因中具有点突变，表现出肥胖，吞噬，短暂性腹泻和胰岛素原过多，表型与人类患者特征一致。该突变导致pV96L氨基酸取代，并改变了小鼠外显子3的第一个核苷酸，导致该外显子的跳跃和纯合子的全长转录本很少。外显子3缺失的蛋白或96L蛋白的过表达导致ER保留在Neuro2a细胞中。这是第二个显示肥胖表型的Pcsk1小鼠模型，与敲除小鼠等位基因形成对比。该模型将有助于调查由激素处理缺陷引起的内分泌疾病的基础。