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 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

doi:10.1038/s41467-017-01429-z

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

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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 language	English
Article number	1289
Journal	Nature Communications
Volume	8
Issue number	1
Number of pages	11
ISSN	2041-1723
DOIs	https://doi.org/10.1038/s41467-017-01429-z
Publication status	Published - 1 Dec 2017

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Two missense mutations in KCNQ1 cause pituitary hormone deficiency and maternally inherited gingival fibromatosisFinal published version, 5.21 MBLicence: CC BY

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Tommiska, J., Känsäkoski, J., Skibsbye, L., Vaaralahti, K., Liu, X., Lodge, E. J., Tang, C., Yuan, L., Fagerholm, R., Kanters, J. K., Lahermo, P., Kaunisto, M., Keski-Filppula, R., Vuoristo, S., Pulli, K., Ebeling, T., Valanne, L., Sankila, E.-M., Kivirikko, S., ... Raivio, T. (2017). Two missense mutations in KCNQ1 cause pituitary hormone deficiency and maternally inherited gingival fibromatosis. Nature Communications, 8(1), Article 1289. https://doi.org/10.1038/s41467-017-01429-z

Tommiska, J, Känsäkoski, J, Skibsbye, L, Vaaralahti, K, Liu, X, Lodge, EJ, Tang, C, Yuan, L, Fagerholm, R, Kanters, JK, Lahermo, P, Kaunisto, M, Keski-Filppula, R, Vuoristo, S, Pulli, K, Ebeling, T, Valanne, L, Sankila, E-M, Kivirikko, S, Lääperi, M, Casoni, F, Giacobini, P, Phan-Hug, F, Buki, T, Tena-Sempere, M, Pitteloud, N, Veijola, R, Lipsanen-Nyman, M, Kaunisto, K, Mollard, P, Andoniadou, CL, Hirsch, JA, Varjosalo, M, Jespersen, T & Raivio, T 2017, 'Two missense mutations in KCNQ1 cause pituitary hormone deficiency and maternally inherited gingival fibromatosis', Nature Communications, vol. 8, no. 1, 1289. https://doi.org/10.1038/s41467-017-01429-z

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title = "Two missense mutations in KCNQ1 cause pituitary hormone deficiency and maternally inherited gingival fibromatosis",

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.",

author = "Johanna Tommiska and Johanna K{\"a}ns{\"a}koski and Lasse Skibsbye and Kirsi Vaaralahti and Xiaonan Liu and Lodge, {Emily J} and Chuyi Tang and Lei Yuan and Rainer Fagerholm and Kanters, {J{\o}rgen K} and P{\"a}ivi Lahermo and Mari Kaunisto and Riikka Keski-Filppula and Sanna Vuoristo and Kristiina Pulli and Tapani Ebeling and Leena Valanne and Eeva-Marja Sankila and Sirpa Kivirikko and Mitja L{\"a}{\"a}peri and Filippo Casoni and Paolo Giacobini and Franziska Phan-Hug and Tal Buki and Manuel Tena-Sempere and Nelly Pitteloud and Riitta Veijola and Marita Lipsanen-Nyman and Kari Kaunisto and Patrice Mollard and Andoniadou, {Cynthia L} and Hirsch, {Joel A} and Markku Varjosalo and Thomas Jespersen and Taneli Raivio",

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T1 - Two missense mutations in KCNQ1 cause pituitary hormone deficiency and maternally inherited gingival fibromatosis

AU - Tommiska, Johanna

AU - Känsäkoski, Johanna

AU - Skibsbye, Lasse

AU - Vaaralahti, Kirsi

AU - Liu, Xiaonan

AU - Lodge, Emily J

AU - Tang, Chuyi

AU - Yuan, Lei

AU - Fagerholm, Rainer

AU - Kanters, Jørgen K

AU - Lahermo, Päivi

AU - Kaunisto, Mari

AU - Keski-Filppula, Riikka

AU - Vuoristo, Sanna

AU - Pulli, Kristiina

AU - Ebeling, Tapani

AU - Valanne, Leena

AU - Sankila, Eeva-Marja

AU - Kivirikko, Sirpa

AU - Lääperi, Mitja

AU - Casoni, Filippo

AU - Giacobini, Paolo

AU - Phan-Hug, Franziska

AU - Buki, Tal

AU - Tena-Sempere, Manuel

AU - Pitteloud, Nelly

AU - Veijola, Riitta

AU - Lipsanen-Nyman, Marita

AU - Kaunisto, Kari

AU - Mollard, Patrice

AU - Andoniadou, Cynthia L

AU - Hirsch, Joel A

AU - Varjosalo, Markku

AU - Jespersen, Thomas

AU - Raivio, Taneli

PY - 2017/12/1

Y1 - 2017/12/1

N2 - 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.

AB - 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.

U2 - 10.1038/s41467-017-01429-z

DO - 10.1038/s41467-017-01429-z

M3 - Journal article

C2 - 29097701

SN - 2041-1723

VL - 8

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 1289

ER -

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

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