ESPE Yearbook of Paediatric Endocrinology

Brief Summary: This study investigated congenital hypothyroidism (CH) due to dominantly inherited resistance to TSH (RTSH) in 12 unrelated families. It reveals that mutations in a non-coding (TTTG) short tandem repeat (STR) on chromosome 15q cause this condition by activating a thyroid-specific enhancer cluster. Functional studies showed that activation of this enhancer cluster leads to upregulation of the bicistronic MIR7-2/MIR1179 locus, resulting in overexpression of its microRNAs in thyroid cells. This dysregulation probably alters thyroid signaling pathways, with both anti-proliferative and proliferative effects.

The study included genetic analysis of 148 individuals of whom 68 carried mutations. Just like the study by Narumi et al [1], the clinical phenotype of mutation carriers consisted of elevated serum TSH and thyroglobulin levels, in combination with FT4 levels within the reference interval. Also like Narumi et al, several mutation carriers developed enlarged nodular thyroid glands, with three participants requiring thyroid surgery [1].

The studies by Narumi et al and Grasberger et al, both published in the May 2024 issue of Nature Genetics, are the first to report the same novel genetic cause of CH caused by pathogenic variants in non-coding DNA. Narumi et al. suggest that it is a frequent cause of CH with a gland-in-situ, especially when the family history is positive for CH or multinodular goiter. Over the last several years, at least five Mendelian disorders have been linked to mutations in miRNA stem loops [2-5], or deletion of a miRNA cluster [6], but STR mutation-linked RTSH appears to be uniquely caused by abnormal pri-MIR expression. Given that 98-99% of the human genome consist of non-coding DNA, it is likely that many more conditions - including CH - will be explained in this way in the coming years.

References: 1. Satoshi Narumi et al. Functional variants in a TTTG microsatellite on 15q26.1 cause familial nonautoimmune thyroid abnormalities. Nat Genet. 2024 May;56(5):869-876. doi: 10.1038/s41588-024-01735-5. Epub 2024 May 7. PMID: 387148682. Mencía A, Modamio-Høybjør S, Redshaw N, Morín M, Mayo-Merino F, Olavarrieta L, Aguirre LA, del Castillo I, Steel KP, Dalmay T, Moreno F, Moreno-Pelayo MA. Mutations in the seed region of human miR-96 are responsible for nonsyndromic progressive hearing loss. Nat Genet. 2009 May;41(5):609-13. doi: 10.1038/ng.355. Epub 2009 Apr 12. PMID: 193634793. Hughes AE, Bradley DT, Campbell M, Lechner J, Dash DP, Simpson DA, Willoughby CE. Mutation altering the miR-184 seed region causes familial keratoconus with cataract. Am J Hum Genet. 2011 Nov 11;89(5):628-33. doi: 10.1016/j.ajhg.2011.09.014. Epub 2011 Oct 11. PMID: 219962754. MiR-204 is responsible for inherited retinal dystrophy associated with ocular coloboma Affiliations Expand. Ivan Conte, Kristen D Hadfield, Sara Barbato, Sabrina Carrella, Mariateresa Pizzo, Rajeshwari S Bhat, Annamaria Carissimo, Marianthi Karali, Louise F Porter, Jill Urquhart, Sofie Hateley, James O’Sullivan, Forbes D C Manson, Stephan C F Neuhauss, Sandro Banfi, Graeme C M Black. Proc Natl Acad Sci U S A. 2015 Jun 23;112(25):E3236-45. doi: 10.1073/pnas.1401464112. Epub 2015 Jun 8. PMID: 260562855. Giedre Grigelioniene, Hiroshi I Suzuki, Fulya Taylan, Fatemeh Mirzamohammadi, Zvi U Borochowitz, Ugur M Ayturk, Shay Tzur, Eva Horemuzova, Anna Lindstrand, Mary Ann Weis, Gintautas Grigelionis, Anna Hammarsjö, Elin Marsk, Ann Nordgren, Magnus Nordenskjöld, David R Eyre, Matthew L Warman, Gen Nishimura, Phillip A Sharp, Tatsuya Kobayashi. Gain-of-function mutation of microRNA-140 in human skeletal dysplasia. Nat Med. 2019 Apr;25(4):583-590. doi: 10.1038/s41591-019-0353-2. Epub 2019 Feb 25. PMID: 308045146. Loïc de Pontual, Evelyn Yao, Patrick Callier, Laurence Faivre, Valérie Drouin, Sandra Cariou, Arie Van Haeringen, David Geneviève, Alice Goldenberg, Myriam Oufadem, Sylvie Manouvrier, Arnold Munnich, Joana Alves Vidigal, Michel Vekemans, Stanislas Lyonnet, Alexandra Henrion-Caude, Andrea Ventura, Jeanne Amiel. Germline deletion of the miR-17~92 cluster causes skeletal and growth defects in humans. Nat Genet. 2011 Sep 4;43(10):1026-30. doi: 10.1038/ng.915. PMID: 21892160