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

Author

Listed:
  • Johanna Tommiska

    (University of Helsinki
    Helsinki University Central Hospital (HUCH))

  • Johanna Känsäkoski

    (University of Helsinki)

  • Lasse Skibsbye

    (University of Copenhagen)

  • Kirsi Vaaralahti

    (University of Helsinki)

  • Xiaonan Liu

    (University of Helsinki)

  • Emily J. Lodge

    (King’s College London)

  • Chuyi Tang

    (University of Copenhagen)

  • Lei Yuan

    (University of Copenhagen)

  • Rainer Fagerholm

    (University of Helsinki
    HUCH)

  • Jørgen K. Kanters

    (University of Copenhagen
    Herlev & Gentofte University Hospitals, University of Copenhagen)

  • Päivi Lahermo

    (University of Helsinki)

  • Mari Kaunisto

    (University of Helsinki)

  • Riikka Keski-Filppula

    (Oulu University Hospital)

  • Sanna Vuoristo

    (University of Helsinki)

  • Kristiina Pulli

    (University of Helsinki)

  • Tapani Ebeling

    (Oulu University Hospital, Finland and Research Unit of Internal Medicine, University of Oulu)

  • Leena Valanne

    (Helsinki Medical Imaging Center, HUCH)

  • Eeva-Marja Sankila

    (HUCH)

  • Sirpa Kivirikko

    (HUCH)

  • Mitja Lääperi

    (University of Helsinki)

  • Filippo Casoni

    (Development and Plasticity of the Neuroendocrine Brain
    University of Lille, School of Medicine)

  • Paolo Giacobini

    (Development and Plasticity of the Neuroendocrine Brain
    University of Lille, School of Medicine)

  • Franziska Phan-Hug

    (University Hospital Lausanne (CHUV))

  • Tal Buki

    (George S. Wise Faculty of Life Sciences, Institute of Structural Biology)

  • Manuel Tena-Sempere

    (Physiology and Immunology, University of Córdoba
    Instituto Maimonides de Investigacion Biomedica (IMIBIC/HURS)
    CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III)

  • Nelly Pitteloud

    (University Hospital Lausanne (CHUV))

  • Riitta Veijola

    (Oulu University Hospital
    PEDEGO Research Center, Medical Research Center, University of Oulu)

  • Marita Lipsanen-Nyman

    (Helsinki University Central Hospital (HUCH))

  • Kari Kaunisto

    (Oulu University Hospital)

  • Patrice Mollard

    (IGF, CNRS, INSERM, Univ. Montpellier)

  • Cynthia L. Andoniadou

    (King’s College London
    Technische Universität Dresden, Fetscherstraße 74)

  • Joel A. Hirsch

    (George S. Wise Faculty of Life Sciences, Institute of Structural Biology)

  • Markku Varjosalo

    (University of Helsinki)

  • Thomas Jespersen

    (University of Copenhagen)

  • Taneli Raivio

    (University of Helsinki
    Helsinki University Central Hospital (HUCH))

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.

Suggested Citation

  • 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 , 2017. "Two missense mutations in KCNQ1 cause pituitary hormone deficiency and maternally inherited gingival fibromatosis," Nature Communications, Nature, vol. 8(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_s41467-017-01429-z
    DOI: 10.1038/s41467-017-01429-z
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