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

• Published in: Nature communications 2017-11, Vol.8 (1), p.1289-11, Article 1289
• Main Authors: Tommiska, Johanna, Känsäkoski, Johanna, Skibsbye, Lasse, Vaaralahti, Kirsi, Liu, Xiaonan, Lodge, Emily J., Tang, Chuyi, Yuan, Lei, Fagerholm, Rainer, Kanters, Jørgen K., Lahermo, Päivi, Kaunisto, Mari, Keski-Filppula, Riikka, Vuoristo, Sanna, Pulli, Kristiina, Ebeling, Tapani, Valanne, Leena, Sankila, Eeva-Marja, Kivirikko, Sirpa, Lääperi, Mitja, Casoni, Filippo, Giacobini, Paolo, Phan-Hug, Franziska, Buki, Tal, Tena-Sempere, Manuel, Pitteloud, Nelly, Veijola, Riitta, Lipsanen-Nyman, Marita, Kaunisto, Kari, Mollard, Patrice, Andoniadou, Cynthia L., Hirsch, Joel A., Varjosalo, Markku, Jespersen, Thomas, Raivio, Taneli
• Format: Article
• Language: English
• Subjects: 631/208/2489/144; 631/208/737; 692/308/2056; Aberration; Adolescent; Adrenocorticotropic hormone; Adrenocorticotropic Hormone - metabolism; Adult; Alleles; Amino Acid Substitution; Animals; Arrhythmia; Arrhythmias, Cardiac - genetics; Child; Child, Preschool; Female; Fibromatosis, Gingival - genetics; Fibromatosis, Gingival - metabolism; Genomes; Gingiva; Gingival fibromatosis; Growth hormone-releasing hormone; Growth hormones; Growth rate; Heart diseases; Human Growth Hormone - deficiency; Humanities and Social Sciences; Humans; Hypothalamus; KCNQ1 Potassium Channel - chemistry; KCNQ1 Potassium Channel - genetics; KCNQ1 Potassium Channel - metabolism; KCNQ1 protein; Linkage analysis; Male; Maternal Inheritance - genetics; Mice; Middle Aged; Missense mutation; Models, Molecular; multidisciplinary; Mutation; Mutation, Missense; Patients; Pedigree; Physical growth; Pituitary; Pituitary hormones; Potassium; Potassium channels (voltage-gated); Protein Interaction Maps; Recombinant Proteins - chemistry; Recombinant Proteins - genetics; Recombinant Proteins - metabolism; Science; Science (multidisciplinary); Secretion; Young Adult
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-017-01429-z

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. Growth retardation is most commonly caused by genetic defects in the growth hormone pathway. Here, in families with growth retardation and gingival fibromatosis, the authors identify mutations in the potassium channel gene KCNQ1 that cause electrophysiological aberrations and altered ACTH secretion in vitro.