Department of Genetics, Ghent University, Ghent, Belgium; Department of Human Genetics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, the Netherlands.
Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, PA, USA.
Clin Chim Acta. 2022 Jul 1;532:79-83. doi: 10.1016/j.cca.2022.05.016. Epub 2022 May 24.
A hitherto undescribed form of diabetes mellitus type 2 is reported in a Flemish family. In these patients, markedly elevated gastrin levels were observed, which could not be linked to gastrointestinal symptoms.
Gel permeation chromatography was performed for gastrin, insulin, and proinsulin. Proprotein convertase subtilisin/kexin type (PCSK1 and PCSK2)] were sequenced. Whole-exome sequencing was performed on the genomic DNA extracted from leukocytes of the proband of the family.
Gel permeation chromatography revealed that the apparent hypergastrinemia was caused by the accumulation of biologically inactive progastrin. Besides, high serum concentrations of proinsulin and intact fibroblast growth factor 23 (FGF23) were also detected. Sequencing of PCSK1 and PCSK2 genes did not reveal any mutations in these genes. Whole exome sequencing revealed a c.1150C > T (p.Pro384Ser) mutation in G protein-coupled receptor kinase 6 (GRK6), which cosegregated with the disease. Expression of the mutant enzyme in mammalian cells revealed that it was mislocalized compared to the wild-type GRK6.
In the affected patients, prohormone processing is impaired likely due to the altered function of mutant GRK6. Delayed pro-insulin processing causes hypoglycaemia episodes a couple of hours following meals. In addition, increased plasma concentrations of progastrin and intact FGF23 in the affected individuals can be explained by incomplete processing of the precursor hormones.
报道了一个弗拉芒家族中从未描述过的 2 型糖尿病形式。在这些患者中，观察到胃泌素水平显著升高，但与胃肠道症状无关。
进行了胃泌素、胰岛素和胰岛素原的凝胶渗透色谱分析。对前蛋白转化酶枯草溶菌素/柯萨奇蛋白酶 1 和 2（PCSK1 和 PCSK2）进行了测序。对来自家族先证者白细胞的基因组 DNA 进行了全外显子组测序。
凝胶渗透色谱显示，明显的高胃泌素血症是由生物活性无活性的前胃泌素积累引起的。此外，还检测到高血清浓度的胰岛素原和完整的成纤维细胞生长因子 23（FGF23）。PCSK1 和 PCSK2 基因测序未发现这些基因的任何突变。全外显子组测序显示 G 蛋白偶联受体激酶 6（GRK6）中的 c.1150C>T（p.Pro384Ser）突变，该突变与疾病共分离。与野生型 GRK6 相比，突变酶在哺乳动物细胞中的表达显示其定位错误。
在受影响的患者中，前激素加工受损可能是由于突变的 GRK6 功能改变所致。胰岛素原加工延迟导致餐后几小时出现低血糖发作。此外，受影响个体中升高的血浆胃泌素和完整 FGF23 浓度可以用前体激素加工不完全来解释。
