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

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 LääperiFilippo 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*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

31 Scopus citations

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.

Original languageEnglish
Article number1289
JournalNature Communications
Volume8
Issue number1
DOIs
StatePublished - 1 Dec 2017

Funding

FundersFunder number
ANR-14-CE12-0015-01
Deutsche Israel Program
Guy’s and St. Thomas
King’s Bioscience Institute
Helsingin ja Uudenmaan Sairaanhoitopiiri2010307
Jalmari ja Rauha Ahokkaan Säätiö
Seventh Framework Programme251413
Medical Research CouncilMR/L016729/1
European Cooperation in Science and TechnologyBM1105
Deutsche Forschungsgemeinschaft
Agence Nationale de la Recherche
Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung135648, 31003A
Academy of Finland138124, 294173
Emil Aaltosen Säätiö2170
Danmarks Frie ForskningsfondDFF-1331-00313B
Ministerio de Ciencia e InnovaciónBFI-2014-57581-P
Lastentautien Tutkimussäätiö7495
Sigrid Juséliuksen Säätiö2613
Paulon Säätiö
European Regional Development Fund
Novo Nordisk Fonden4761

    Fingerprint

    Dive into the research topics of 'Two missense mutations in KCNQ1 cause pituitary hormone deficiency and maternally inherited gingival fibromatosis'. Together they form a unique fingerprint.

    Cite this