University of Oulu

Tommiska, J., Känsäkoski, J., Skibsbye, L., Vaaralahti, K., Liu, X., Lodge, E. J., … Raivio, T. (2017). Two missense mutations in KCNQ1 cause pituitary hormone deficiency and maternally inherited gingival fibromatosis. Nature Communications, 8(1).

Two missense mutations in KCNQ1 cause pituitary hormone deficiency and maternally inherited gingival fibromatosis

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Author: Tommiska, Johanna1,2; Känsäkoski, Johanna1; Skibsbye, Lasse3;
Organizations: 1Faculty of Medicine, Department of Physiology, University of Helsinki, 00014, Helsinki, Finland
2Children’s Hospital, Pediatric Research Center, Helsinki University Central Hospital (HUCH), 00029, Helsinki, Finland
3Department of Biomedical Sciences, University of Copenhagen, 2200, Copenhagen N, Denmark
4Institute of Biotechnology, Biocenter 3, University of Helsinki, 00014, Helsinki, Finland
5Centre for Craniofacial and Regenerative Biology, King’s College London, Floor 27 Tower Wing, Guy’s Campus, London, SE1 9RT, UK
6Department of Obstetrics and Gynecology, HUCH, 00029, Helsinki, Finland
7Laboratory of Experimental Cardiology, Department of Biomedical Sciences, University of Copenhagen, 22000, Copenhagen, Denmark
8Department of Cardiology, Herlev & Gentofte University Hospitals, University of Copenhagen, 22000, Copenhagen, Denmark
9Institute for Molecular Medicine Finland (FIMM), Helsinki Institute of Life Science HiLIFE, University of Helsinki, 00014, Helsinki, Finland
10Department of Clinical Genetics, Oulu University Hospital, 90029, Oulu, Finland
11Department of Medicine, Oulu University Hospital, Finland and Research Unit of Internal Medicine, University of Oulu, 90014, Oulu, Finland
12Helsinki Medical Imaging Center, HUCH, 00029, Helsinki, Finland
13Department of Ophthalmology, HUCH, 00029, Helsinki, Finland
14Department of Clinical Genetics, HUCH, 00029, Helsinki, Finland
15Inserm U1172, Jean-Pierre Aubert Research Center, Development and Plasticity of the Neuroendocrine Brain, 59045, Lille, France
16University of Lille, School of Medicine, 59045, Lille, France
17Pediatrics, Division of Pediatric Endocrinology, Diabetology and Obesity, University Hospital Lausanne (CHUV), 1011, Lausanne, Switzerland
18Department of Biochemistry and Molecular Biology, George S. Wise Faculty of Life Sciences, Institute of Structural Biology, 69978, Ramat Aviv, Israel
19Department of Cell Biology, Physiology and Immunology, University of Córdoba, 14071, Cordoba, Spain
20Instituto Maimonides de Investigacion Biomedica (IMIBIC/HURS), 14004, Cordoba, Spain
21CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, 28029, Madrid, Spain
22Department of Children and Adolescents, Oulu University Hospital, 90029, Oulu, Finland
23Department of Pediatrics, PEDEGO Research Center, Medical Research Center, University of Oulu, 90014, Oulu, Finland
24IGF, CNRS, INSERM, Univ. Montpellier, F-34094, Montpellier, France
25Department of Internal Medicine III, Technische Universität Dresden, Fetscherstraße 74, 01307, Dresden, Germany
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 5.2 MB)
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Language: English
Published: Springer Nature, 2017
Publish Date: 2019-08-12


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.

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Series: Nature communications
ISSN: 2041-1723
ISSN-E: 2041-1723
ISSN-L: 2041-1723
Volume: 8
Article number: 1289
DOI: 10.1038/s41467-017-01429-z
Type of Publication: A1 Journal article – refereed
Field of Science: 3111 Biomedicine
3121 General medicine, internal medicine and other clinical medicine
Funding: Ms. Lea Puhakka is thanked for skillful technical assistance. Dr. Päivi Miettinen isthanked for commenting on the manuscript. This work was supported by the Academyof Finland (138124 to J.T., 251413 to T.R., 294173 to M.V.), Foundation for PediatricResearch (7495 to T.R.), Sigrid Juselius Foundation (2613 to T.R.), Emil AaltonenFoundation (2170 to T.R.), Novo Nordisk Foundation (4761 to T.R.), Helsinki UniversityCentral Hospital research funds (2010307), Jalmari and Rauha Ahokas Foundation (to J.T.), Paulo Foundation (to J.T.), Danish Council for Independent Research (DFF-1331-00313B to T.J.), Agence Nationale de la Recherche, ANR, France (ANR-14-CE12-0015-01 RoSes and GnRH to P.G.: ANR 12 BSV1 0032 Peri-Pulse to both P.G. and P.M.),Swiss National Science Foundation grants (31003A, 135648 to N.P.), Spanish Ministry ofScience (Grant BFI-2014-57581-P to M.T.-S., co-funded with EU funds from FEDERProgram), COST grant (Action BM1105), Deutsche Israel Program grant (DFG, to J.A.H.), the King’s Bioscience Institute and the Guy’s and St. Thomas’Charity Prize Ph.D.Programme in Biomedical and Translational Science (to E.J.L.), and Medical ResearchCouncil (MR/L016729/1 to C.L.A.).
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