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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 ?-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.

SUBMITTER: Tommiska J

PROVIDER: S-EPMC5668380 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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

Tommiska Johanna J Känsäkoski Johanna J Skibsbye Lasse L Vaaralahti Kirsi K Liu Xiaonan X Lodge Emily J EJ Tang Chuyi C Yuan Lei L Fagerholm Rainer R Kanters Jørgen K JK Lahermo Päivi P Kaunisto Mari M Keski-Filppula Riikka R Vuoristo Sanna S Pulli Kristiina K Ebeling Tapani T Valanne Leena L Sankila Eeva-Marja EM Kivirikko Sirpa S Lääperi Mitja M Casoni Filippo F Giacobini Paolo P Phan-Hug Franziska F Buki Tal T Tena-Sempere Manuel M Pitteloud Nelly N Veijola Riitta R Lipsanen-Nyman Marita M Kaunisto Kari K Mollard Patrice P Andoniadou Cynthia L CL Hirsch Joel A JA Varjosalo Markku M Jespersen Thomas T Raivio Taneli T

Nature communications 20171103 1

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 ...[more]

PMID: 29097701

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Project description:Gingival fibromatosis is a rare and heterogeneous group of disorders that develop as slowly progressive, local or diffuse enlargements within marginal and attached gingiva or interdental papilla. In severe cases, the excess tissue may cover the crowns of the teeth, thus causing functional, esthetic, and periodontal problems, such as bone loss and bleeding, due to the presence of pseudopockets and plaque accumulation. It affects both genders equally. Hereditary, drug-induced, and idiopathic gingival overgrowth have been reported. Hereditary gingival fibromatosis can occur as an isolated condition or as part of a genetic syndrome. The pathologic manifestation of gingival fibromatosis comprises excessive accumulation of extracellular matrix proteins, of which collagen type I is the most prominent example. Mutation in the Son-of-Sevenless-1 gene has been suggested as one possible etiological cause of isolated (non-syndromic) hereditary gingival fibromatosis, but mutations in other genes are also likely to be involved, given the heterogeneity of this condition. The most attractive concept of mechanism for drug-induced gingival overgrowth is epithelial-to-mesenchymal transition, a process in which interactions between gingival cells and the extracellular matrix are weakened as epithelial cells transdifferentiate into fibrogenic fibroblast-like cells. The diagnosis is mainly made on the basis of the patient's history and clinical features, and on histopathological evaluation of affected gingiva. Early diagnosis is important, mostly to exclude oral malignancy. Differential diagnosis comprises all pathologies in the mouth with excessive gingival overgrowth. Hereditary gingival fibromatosis may present as an autosomal-dominant or less commonly autosomal-recessive mode of inheritance. If a systemic disease or syndrome is suspected, the patient is directed to a geneticist for additional clinical examination and specialized diagnostic tests. Treatments vary according to the type of overgrowth and the extent of disease progression, thus, scaling of teeth is sufficient in mild cases, while in severe cases surgical intervention is required. Prognosis is precarious and the risk of recurrence exists.

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

Publications

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

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