Faculty of Medicine, Department of Physiology, University of Helsinki, 00014, Helsinki, Finland.
Children's Hospital, Pediatric Research Center, Helsinki University Central Hospital (HUCH), 00029, Helsinki, Finland.
Nat Commun. 2017 Nov 3;8(1):1289. doi: 10.1038/s41467-017-01429-z.
Familial growth hormone deficiency provides an opportunity to identify new genetic causes of short stature. Here we combine linkage analysis with whole-genome resequencing in patients with growth hormone deficiency and maternally inherited gingival fibromatosis. We report that patients from three unrelated families harbor either of two missense mutations, c.347G>T p.(Arg116Leu) or c.1106C>T p.(Pro369Leu), in KCNQ1, a gene previously implicated in the long QT interval syndrome. Kcnq1 is expressed in hypothalamic GHRH neurons and pituitary somatotropes. Co-expressing KCNQ1 with the KCNE2 β-subunit shows that both KCNQ1 mutants increase current levels in patch clamp analyses and are associated with reduced pituitary hormone secretion from AtT-20 cells. In conclusion, our results reveal a role for the KCNQ1 potassium channel in the regulation of human growth, and show that growth hormone deficiency associated with maternally inherited gingival fibromatosis is an allelic disorder with cardiac arrhythmia syndromes caused by KCNQ1 mutations.
家族性生长激素缺乏症为识别身材矮小的新遗传病因提供了机会。在这里，我们将生长激素缺乏症和遗传性牙龈纤维瘤病患者的连锁分析与全基因组重测序相结合。我们报告说，来自三个无关联家族的患者携带 KCNQ1 中的两种错义突变之一，c.347G>T p.(Arg116Leu)或 c.1106C>T p.(Pro369Leu)，该基因先前与长 QT 间隔综合征有关。Kcnq1 在下丘脑 GHRH 神经元和垂体生长激素细胞中表达。与 KCNE2 β 亚基共表达 KCNQ1 表明，两种 KCNQ1 突变体在膜片钳分析中增加电流水平，并与 AtT-20 细胞中垂体激素分泌减少有关。总之，我们的研究结果揭示了 KCNQ1 钾通道在人类生长调节中的作用，并表明与遗传性牙龈纤维瘤病相关的生长激素缺乏症是一种等位基因疾病，与 KCNQ1 突变引起的心律失常综合征有关。
