Two missense mutations in KCNQ1 cause pituitary hormone deficiency and maternally inherited gingival fibromatosis
Year: 2017
Type: article
Study design: Observational Study
Abstract: 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.
Source: Nature Communications
Authors: Johanna Tommiska, Johanna Känsäkoski, Lasse Skibsbye, Kirsi Vaaralahti, Xiaonan Liu, Emily J. Lodge, Chuyi Tang, Lei Yuan, Rainer Fagerholm, Jørgen K. Kanters, Päivi Lahermo, Mari Kaunisto, Riikka Keski-Filppula, Sanna Vuoristo, Kristiina Pulli, Tapani Ebeling, Leena Valanne, Eeva-Marja Sankila, Sirpa Kivirikko, Mitja Lääperi, Filippo Casoni, Paolo Giacobini, Franziska Phan-Hug, Tal Buki, Manuel Tena-Sempere, Nelly Pitteloud, Riitta Veijola, Marita Lipsanen-Nyman, Kari Kaunisto, Patrice Mollard, Cynthia L. Andoniadou, Joel A. Hirsch, Markku Varjosalo, Thomas Jespersen, Taneli Raivio
Institutions: University of Helsinki, Helsinki University Hospital, Helsinki Children's Hospital, University of Copenhagen, King's College London, Gentofte Hospital, Institute for Molecular Medicine Finland, HiLIFE – Elämäntieteiden Instituutti, Oulu University Hospital, University of Oulu, Inserm, Université de Lille, Centre de Recherche Jean Pierre Aubert, Lille Neurosciences & Cognition, Centre Hospitalier Universitaire Vaudois, Tel Aviv University, Instituto de Salud Carlos III, Instituto Maimónides de Investigación Biomédica de Córdoba, University of Córdoba, Centre National de la Recherche Scientifique, Université de Montpellier, Institut de Génomique Fonctionnelle, Technische Universität Dresden
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $6,990
Funders: National Science Foundation, Helsingin ja Uudenmaan Sairaanhoitopiiri, Jalmari ja Rauha Ahokkaan Säätiö, Deutsche Forschungsgemeinschaft, Agence Nationale de la Recherche, Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung, Academy of Finland, Novo Nordisk, Emil Aaltosen Säätiö, Danmarks Frie Forskningsfond, Lastentautien Tutkimussäätiö, Novo Nordisk Fonden, Medical Research Council
Awards: G1699780958, G1997641753, G3925944279, The Neuroendocrine Control of Human Reproduction, Pericytes and stimulus-secretion-coupling in vivo, G544591541, G5891103467, Function and Regulation of the Pituitary Stem Cell Compartment in Mammals, G7652945577, The role of semaphorin-signaling in the neuroendocrine control of reproduction
OpenAlex ID: W2766916632