ESPE Abstracts (2019) 92 S5.3

The Role of KCNQ1 in Pituitary Development

Taneli Raivio


Translational Stem Cell Biology and Metabolism Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland. Pediatric Research Center, Children's Hospital, Helsinki University Hospital, Helsinki, Finland


Childhood onset of growth hormone deficiency (GHD) is a clinically heterogeneous condition and defining its cause is important for diagnostics and treatment. The most common genes implicated in the genetic etiology of growth hormone deficiency (GHD) are GH1 (MIM: 139250), encoding growth hormone (GH), and GHRHR (MIM: 139191), encoding the receptor for GHRH. GHD may also result from mutations in genes that encode transcription factors involved in pituitary development: OTX2 (MIM: 600037), SOX2 (MIM: 184429), SOX3 (MIM: 313430), LHX3 (MIM: 600577), HESX1 (MIM: 601802), PITX2 (MIM: 601542), PROP1 (MIM: 601538), POU1F1 (MIM: 173110), and TCF7L1 (MIM:604652) (1-3). Additionally, mutations in RNCP3, a gene which encodes the minor spliceosomal protein U11/U12-65K, are shown to underlie growth hormone deficiency (4). Some of the mutations in the genes above are associated with additional pituitary hormone deficiencies and developmental abnormalities, such as variants of septo-optic dysplasia (MIM: 182230), ocular defects, ectopic posterior pituitary, skeletal defects, and intellectual impairment. We have recently shown that two missense mutations, p.(Arg116Leu) and p.(Pro369Leu) in KCNQ1, a gene implicated in cardiac arrhythmias, underlie growth hormone deficiency and maternally inherited craniofacial phenotype with gingival fibromatosis (5). Subsequently, children with long QT syndrome due to loss-of-function mutations in KCNQ1 were shown to grow normally (6), and KCNQ1 mutations were not found in a cohort of 53 patients with GH-secreting pituitary adenomas (7). In conclusion, the role of ion channels in the regulation of human growth has started to emerge. My laboratory currently focuses in elucidating the molecular mechanism by which the two KCNQ1 mutations cause pituitary hormone deficiency.

1. Alatzoglou, K. S., et al Endocr. Rev. 35: 376–432 (2014). 2. Gaston-Massuet, C. et al. Proc. Natl Acad. Sci. USA. 113: E548–E557 (2016). 3. Fang Q. et al. Endocr Rev. 37: 636–675 (2016) 4. Argente J. et al.. EMBO Mol Med. 6: 299-306 (2014). 5. Tommiska J. et al. Nat Commun. 8:1289 (2017). 6. Huttunen H. Front Endocrinol 9:194 (2018) 7. Iivonen AP. et al. Endocr Connect 7:645-652 (2018).

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