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Nat Commun. 2017 Nov 3;8(1):1289. doi: 10.1038/s41467-017-01429-z.

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

Author information

1
Faculty of Medicine, Department of Physiology, University of Helsinki, 00014, Helsinki, Finland.
2
Children's Hospital, Pediatric Research Center, Helsinki University Central Hospital (HUCH), 00029, Helsinki, Finland.
3
Department of Biomedical Sciences, University of Copenhagen, 2200, Copenhagen N, Denmark.
4
Institute of Biotechnology, Biocenter 3, University of Helsinki, 00014, Helsinki, Finland.
5
Centre for Craniofacial and Regenerative Biology, King's College London, Floor 27 Tower Wing, Guy's Campus, London, SE1 9RT, UK.
6
Department of Obstetrics and Gynecology, HUCH, 00029, Helsinki, Finland.
7
Laboratory of Experimental Cardiology, Department of Biomedical Sciences, University of Copenhagen, 22000, Copenhagen, Denmark.
8
Department of Cardiology, Herlev & Gentofte University Hospitals, University of Copenhagen, 22000, Copenhagen, Denmark.
9
Institute for Molecular Medicine Finland (FIMM), Helsinki Institute of Life Science HiLIFE, University of Helsinki, 00014, Helsinki, Finland.
10
Department of Clinical Genetics, Oulu University Hospital, 90029, Oulu, Finland.
11
Department of Medicine, Oulu University Hospital, Finland and Research Unit of Internal Medicine, University of Oulu, 90014, Oulu, Finland.
12
Helsinki Medical Imaging Center, HUCH, 00029, Helsinki, Finland.
13
Department of Ophthalmology, HUCH, 00029, Helsinki, Finland.
14
Department of Clinical Genetics, HUCH, 00029, Helsinki, Finland.
15
Inserm U1172, Jean-Pierre Aubert Research Center, Development and Plasticity of the Neuroendocrine Brain, 59045, Lille, France.
16
University of Lille, School of Medicine, 59045, Lille, France.
17
Pediatrics, Division of Pediatric Endocrinology, Diabetology and Obesity, University Hospital Lausanne (CHUV), 1011, Lausanne, Switzerland.
18
Department of Biochemistry and Molecular Biology, George S. Wise Faculty of Life Sciences, Institute of Structural Biology, 69978, Ramat Aviv, Israel.
19
Department of Cell Biology, Physiology and Immunology, University of Córdoba, 14071, Cordoba, Spain.
20
Instituto Maimonides de Investigacion Biomedica (IMIBIC/HURS), 14004, Cordoba, Spain.
21
CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, 28029, Madrid, Spain.
22
Department of Children and Adolescents, Oulu University Hospital, 90029, Oulu, Finland.
23
Department of Pediatrics, PEDEGO Research Center, Medical Research Center, University of Oulu, 90014, Oulu, Finland.
24
IGF, CNRS, INSERM, Univ. Montpellier, F-34094, Montpellier, France.
25
Department of Internal Medicine III, Technische Universität Dresden, Fetscherstraße 74, 01307, Dresden, Germany.
26
Faculty of Medicine, Department of Physiology, University of Helsinki, 00014, Helsinki, Finland. taneli.raivio@helsinki.fi.
27
Children's Hospital, Pediatric Research Center, Helsinki University Central Hospital (HUCH), 00029, Helsinki, Finland. taneli.raivio@helsinki.fi.

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.

PMID:
29097701
PMCID:
PMC5668380
DOI:
10.1038/s41467-017-01429-z
[Indexed for MEDLINE]
Free PMC Article

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