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

Johanna Tommiska; Johanna Kansakoski; Lasse Skibsbye; Kirsi Vaaralahti; Xiaonan Liu; Emily J. Lodge; Chuyi Tang; Lei Yuan; Rainer Fagerholm; Jorgen K. Kanters; Paivi Lahermo; Mari Kaunisto; Riikka Keski-Filppula; Sanna Vuoristo; Kristiina Pulli; Tapani Ebeling; Leena Valanne; Eeva-Marja Sankila; Sirpa Kivirikko; Mitja Laaperi; 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

doi:10.1038/s41467-017-01429-z

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

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

Johanna Tommiska, Johanna Kansakoski, Lasse Skibsbye, Kirsi Vaaralahti, Xiaonan Liu, Emily J. Lodge, Chuyi Tang, Lei Yuan, Rainer Fagerholm, Jorgen K. Kanters, …

Nature communications, Vol.8(1), pp.1289-11

03/11/2017

DOI: https://doi.org/10.1038/s41467-017-01429-z

PMID: 29097701

Résumé

Multidisciplinary Sciences

Science & Technology

Science & Technology - Other Topics

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 beta-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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Titre: Two missense mutations in KCNQ1 cause pituitary hormone deficiency and maternally inherited gingival fibromatosis
Créateurs - sans rôle: Johanna Tommiska - Univ Helsinki, Fac Med, Dept Physiol, Helsinki 00014, Finland
Johanna Kansakoski - Univ Helsinki, Fac Med, Dept Physiol, Helsinki 00014, Finland
Lasse Skibsbye - Univ Copenhagen, Dept Biomed Sci, DK-2200 Copenhagen N, Denmark
Kirsi Vaaralahti - Univ Helsinki, Fac Med, Dept Physiol, Helsinki 00014, Finland
Xiaonan Liu - Univ Helsinki, Inst Biotechnol, Bioctr 3, Helsinki 00014, Finland
Emily J. Lodge - Kings Coll London, Ctr Craniofacial & Regenerat Biol, Floor 27 Tower Wing,Guys Campus, London SE1 9RT, England
Chuyi Tang - Univ Copenhagen, Dept Biomed Sci, DK-2200 Copenhagen N, Denmark
Lei Yuan - Univ Copenhagen, Dept Biomed Sci, DK-2200 Copenhagen N, Denmark
Rainer Fagerholm - Univ Helsinki, Fac Med, Dept Physiol, Helsinki 00014, Finland
Jorgen K. Kanters - Univ Copenhagen, Dept Biomed Sci, Lab Expt Cardiol, DK-22000 Copenhagen, Denmark
Paivi Lahermo - Univ Helsinki, Helsinki Inst Life Sci HiLIFE, Ins Mol Med Finland FIMM, Helsinki 00014, Finland
Mari Kaunisto - University of Helsinki
Riikka Keski-Filppula - Oulu Univ Hosp, Dept Clin Genet, Oulu 90029, Finland
Sanna Vuoristo - Univ Helsinki, Fac Med, Dept Physiol, Helsinki 00014, Finland
Kristiina Pulli - Univ Helsinki, Fac Med, Dept Physiol, Helsinki 00014, Finland
Tapani Ebeling - Univ Oulu, Oulu Univ Hosp, Finland & Res Unit Internal Med, Dept Med, Oulu 90014, Finland
Leena Valanne - HUCH, Helsinki Med Imaging Ctr, Helsinki 00029, Finland
Eeva-Marja Sankila - HUCH, Dept Ophthalmol, Helsinki 00029, Finland
Sirpa Kivirikko - HUCH, Dept Clin Genet, Helsinki 00029, Finland
Mitja Laaperi - Univ Helsinki, Fac Med, Dept Physiol, Helsinki 00014, Finland
Filippo Casoni - INSERM, Jean Pierre Aubert Res Ctr, Dev & Plast Neuroendocrine Brain, U1172, F-59045 Lille, France
Paolo Giacobini - INSERM, Jean Pierre Aubert Res Ctr, Dev & Plast Neuroendocrine Brain, U1172, F-59045 Lille, France
Franziska Phan-Hug - Univ Hosp Lausanne CHUV, Div Pediat Endocrinol Diabetol & Obes, Pediat, CH-1011 Lausanne, Switzerland
Tal Buki - Inst Biol Struct, Dept Biochem & Mol Biol, George S Wise Fac Life Sci, IL-69978 Ramat Aviv, Israel
Manuel Tena-Sempere - Univ Cordoba, Dept Cell Biol Physiol & Immunol, Cordoba 14071, Spain
Nelly Pitteloud - Univ Hosp Lausanne CHUV, Div Pediat Endocrinol Diabetol & Obes, Pediat, CH-1011 Lausanne, Switzerland
Riitta Veijola - Oulu Univ Hosp, Dept Children & Adolescents, Oulu 90029, Finland
Marita Lipsanen-Nyman - HUCH, Childrens Hosp, Pediat Res Ctr, Helsinki 00029, Finland
Kari Kaunisto - Oulu Univ Hosp, Dept Children & Adolescents, Oulu 90029, Finland
Patrice Mollard - Inserm
Cynthia L. Andoniadou - Kings Coll London, Ctr Craniofacial & Regenerat Biol, Floor 27 Tower Wing,Guys Campus, London SE1 9RT, England
Joel A. Hirsch - Inst Biol Struct, Dept Biochem & Mol Biol, George S Wise Fac Life Sci, IL-69978 Ramat Aviv, Israel
Markku Varjosalo - Univ Helsinki, Inst Biotechnol, Bioctr 3, Helsinki 00014, Finland
Thomas Jespersen - Univ Copenhagen, Dept Biomed Sci, DK-2200 Copenhagen N, Denmark
Taneli Raivio - University of Helsinki
Détails de publication: Nature communications, Vol.8(1), pp.1289-11
Éditeur: NATURE PORTFOLIO
Nombre de pages: 11
Note de subvention: NNF15OC0016512 / Novo Nordisk Fonden; Novo Nordisk Foundation MR/L016729/1 / Medical Research Council; UK Research & Innovation (UKRI); Medical Research Council UK (MRC) 138124; 251413 / Academy of Finland (AKA); Research Council of Finland ANR-12-BSV1-0032 / Agence Nationale de la Recherche (ANR) 2010307 / Helsinki University Central Hospital research funds 4761 / Novo Nordisk Foundation ANR-14-CE12-001501; ANR 12 BSV1 0032 / Agence Nationale de la Recherche, ANR, France; Agence Nationale de la Recherche (ANR) DFF-133100313B / Danish Council for Independent Research; Det Frie Forskningsrad (DFF) BFI-2014-57581-P / Spanish Ministry of Science; Spanish Government; Ministry of Science & Innovation, Spain (MICINN) 138124; 251413; 294173 / Academy of Finland; Research Council of Finland
Identifiants: 99162972909311
Unité académique: Institut de Génomique Fonctionnelle - IGF
Langue: English
Type de ressource: Journal article