Functional variants in a TTTG microsatellite on 15q26.1 cause familial nonautoimmune thyroid abnormalities.

Autor: Narumi S; Department of Pediatrics, Keio University School of Medicine, Tokyo, Japan. narumi-s@keio.jp.; Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, Japan. narumi-s@keio.jp., Nagasaki K; Division of Pediatrics, Department of Homeostatic Regulation and Development, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan., Kiriya M; Department of Clinical Laboratory Science, Faculty of Medical Technology, Teikyo University, Tokyo, Japan., Uehara E; Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, Japan., Akiba K; Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, Japan.; Division of Endocrinology and Metabolism, Tokyo Metropolitan Children's Medical Center, Tokyo, Japan., Tanase-Nakao K; Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, Japan., Shimura K; Department of Pediatrics, Keio University School of Medicine, Tokyo, Japan., Abe K; Department of Pediatrics, Keio University School of Medicine, Tokyo, Japan., Sugisawa C; Department of Pediatrics, Keio University School of Medicine, Tokyo, Japan.; Department of Internal Medicine, Ito Hospital, Tokyo, Japan., Ishii T; Department of Pediatrics, Keio University School of Medicine, Tokyo, Japan., Miyako K; Department of Endocrinology and Metabolism, Fukuoka Children's Hospital, Fukuoka, Japan., Hasegawa Y; Division of Endocrinology and Metabolism, Tokyo Metropolitan Children's Medical Center, Tokyo, Japan., Maruo Y; Department of Pediatrics, Shiga University of Medical Science, Otsu, Japan., Muroya K; Department of Endocrinology and Metabolism, Kanagawa Children's Medical Center, Yokohama, Japan., Watanabe N; Department of Internal Medicine, Ito Hospital, Tokyo, Japan., Nishihara E; Center for Excellence in Thyroid Care, Kuma Hospital, Kobe, Japan., Ito Y; Department of Genetic Diagnosis and Laboratory Medicine, Dokkyo Medical University, Mibu, Japan., Kogai T; Department of Genetic Diagnosis and Laboratory Medicine, Dokkyo Medical University, Mibu, Japan., Kameyama K; Department of Pathology, Showa University Northern Yokohama Hospital, Yokohama, Japan., Nakabayashi K; Department of Maternal-Fetal Biology, National Research Institute for Child Health and Development, Tokyo, Japan., Hata K; Department of Maternal-Fetal Biology, National Research Institute for Child Health and Development, Tokyo, Japan.; Department of Human Molecular Genetics, Gunma University Graduate School of Medicine, Maebashi, Japan., Fukami M; Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, Japan., Shima H; Department of Pediatrics, Tohoku University Graduate School of Medicine, Sendai, Japan., Kikuchi A; Department of Pediatrics, Tohoku University Graduate School of Medicine, Sendai, Japan., Takayama J; Department of AI and Innovative Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan.; Department of Integrative Genomics, Tohoku Medical Megabank Organization (ToMMo) Tohoku University, Sendai, Japan.; Statistical Genetics Team, RIKEN Center for Advanced Intelligence Project, Tokyo, Japan., Tamiya G; Department of AI and Innovative Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan.; Department of Integrative Genomics, Tohoku Medical Megabank Organization (ToMMo) Tohoku University, Sendai, Japan.; Statistical Genetics Team, RIKEN Center for Advanced Intelligence Project, Tokyo, Japan., Hasegawa T; Department of Pediatrics, Keio University School of Medicine, Tokyo, Japan.
Jazyk: angličtina
Zdroj: Nature genetics [Nat Genet] 2024 May; Vol. 56 (5), pp. 869-876. Date of Electronic Publication: 2024 May 07.
DOI: 10.1038/s41588-024-01735-5
Abstrakt: Insufficient thyroid hormone production in newborns is referred to as congenital hypothyroidism. Multinodular goiter (MNG), characterized by an enlarged thyroid gland with multiple nodules, is usually seen in adults and is recognized as a separate disorder from congenital hypothyroidism. Here we performed a linkage analysis of a family with both nongoitrous congenital hypothyroidism and MNG and identified a signal at 15q26.1. Follow-up analyses with whole-genome sequencing and genetic screening in congenital hypothyroidism and MNG cohorts showed that changes in a noncoding TTTG microsatellite on 15q26.1 were frequently observed in congenital hypothyroidism (137 in 989) and MNG (3 in 33) compared with controls (3 in 38,722). Characterization of the noncoding variants with epigenomic data and in vitro experiments suggested that the microsatellite is located in a thyroid-specific transcriptional repressor, and its activity is disrupted by the variants. Collectively, we presented genetic evidence linking nongoitrous congenital hypothyroidism and MNG, providing unique insights into thyroid abnormalities.
(© 2024. The Author(s).)
Databáze: MEDLINE
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