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Молекулярно-генетические основы дисгенезии щитовидной железы

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Врожденный гипотиреоз - гетерогенная группа заболеваний, объединенных общим признаком - снижением функции щитовидной железы (ЩЖ) к моменту рождения. 80-85% случаев заболевания обусловлены различными вариантами нарушения органогенеза ЩЖ. На сегодняшний день в литературе описано 5 генов: i>TSHR, PAX8, FOXE1, NKX2-1, NKX2-5,/i> задействованных в патогенезе дисгенезии щитовидной железы. Цель. Оценить частоту мутаций в генах i>TSHR, PAX8, FOXE1, NKX2-1, NKX2-5/i> среди пациентов с тяжелым врожденным гипотиреозом. Методы. В исследование включен 161 пациент с врожденным гипотиреозом (64 мальчика, 97 девочек) с уровнем тиреотропного гормона по данным скрининга или ретестирования более 90 мМЕ/л. При ультразвуковом исследовании ЩЖ у 138 обследуемых диагностированы различные варианты дисгенезии, у 23 пациентов объем железы соответствовал нормальным значениям относительно площади поверхности тела. Для молекулярно-генетического анализа применялся метод высокопроизводительного параллельного секвенирования. Секвенирование осуществлялось на полупроводниковом секвенаторе PGM (Ion Torrent, Life Technologies, США) с использованием панели праймеров “Гипотиреоз” (Custom DNA Panel). Оценка патогенности мутаций осуществлялась согласно последним международным рекомендациям (ACMG, 2015). Результаты. Мутации в генах, приводящие к дисгенезии щитовидной железы, были выявлены у 13 пациентов (8,1%, 13/161): i>TSHR/i>, i>n/i> = 6; i>NKX2-1/i>, i>n/i> = 3; i>NKX2-5/i>, i>n/i> = 1; i>PAX8/i>, i>n/i> = 3; i>FOXE1/i>, i>n/i> = 0. Заключение. Мутации в генах, обусловливающие развитие дисгенезии щитовидной железы, являются редкой патологией. Среди наших пациентов наибольшее количество мутаций выявлено в гене i>TSHR/i>.

Ключевые слова:
дисгенезия, высокопроизводительное параллельное секвенирование, врожденный гипотиреоз, thyroid dysgenesis, next generation sequencing, congenital hypothyroidism

Литература:
1.Devos H, Rodd C, Gagne N, et al. A search for the possible molecular mechanisms of thyroid dysgenesis: sex ratios and associated malformations. J Clin Endocrinol Metab. 1999;84(7): 2502-2506. doi: 10.1210/jcem.84.7.5831.
2.Bubuteishvili L, Garel C, Czernichow P, Leger J. Thyroid abnormalities by ultrasonography in neonates with congenital hypothyroidism. J Pediatr. 2003;143(6):759-764. doi: 10.1067/s0022-3476(03)00537-7.
3.Van Vliet G, Deladoey J. Hypothyroidism in infants and children: congenital hypothyroidism. In: Braverman LE, Cooper D, editors. Werner & Ingbar’s the thyroid: a fundamental and clinical text. 10th ed. Philadelphia: Lippincott Williams and Wilkins; 2012. p. 790-802.
4.Rastogi MV, LaFranchi SH. Congenital hypothyroidism. Orphanet J Rare Dis. 2010;5(1):17. doi: 10.1186/1750-1172-5-17.
5.Szinnai G. Clinical genetics of congenital hypothyroidism. Endocr Dev. 2014;26:60-78. doi: 10.1159/000363156.
6.Lints TJ, Parsons LM, Hartley L, et al. Nkx-2.5: a novel murine homeobox gene expressed in early heart progenitor cells and their myogenic descendants. Development. 1993;119(2):419-431.
7.Dentice M, Cordeddu V, Rosica A, et al. Missense mutation in the transcription factor NKX2-5: a novel molecular event in the pathogenesis of thyroid dysgenesis. J Clin Endocrinol Metab. 2006;91(4): 1428-1433. doi: 10.1210/jc.2005-1350.
8.Wang K, Li M, Hakonarson H. ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data. Nucleic Acids Res. 2010;38(16):e164. doi: 10.1093/nar/gkq603.
9.Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015; 17(5):405-424. doi: 10.1038/gim.2015.30.
10.den Dunnen JT, Dalgleish R, Maglott DR, et al. HGVS Recommendations for the Description of Sequence Variants: 2016 Update. Hum Mutat. 2016;37(6):564-569. doi: 10.1002/humu.22981.
11.Sunthornthepvarakui T, Gottschalk ME, Hayashi Y, Refetoff S. Brief report: resistance to thyrotropin caused by mutations in the thyrotropin-receptor gene. N Engl J Med. 1995;332(3):155-160. doi: 10.1056/NEJM199501193320305.
12.Макрецкая НА, Калинченко НЮ, Васильев ЕВ, и др. Клинический случай врожденного гипотиреоза, обусловленного дефектом гена NKX2-1. // Проблемы эндокринологии. - 2016. - Т. 62. - №3. - С. 21-24. doi: 10.14341/probl201662321-24.
13.Gras D, Jonard L, Roze E, et al. Benign hereditary chorea: phenotype, prognosis, therapeutic outcome and long term follow-up in a large series with new mutations in the TITF1/NKX2-1 gene. J Neurol Neurosurg Psychiatry. 2012;83(10):956-962. doi: 10.1136/jnnp-2012-302505.
14.Montanelli L, Tonacchera M. Genetics and phenomics of hypothyroidism and thyroid dys- and agenesis due to PAX8 and TTF1 mutations. Mol Cell Endocrinol. 2010;322(1-2):64-71. doi: 10.1016/j.mce.2010.03.009.
15.Narumi S, Muroya K, Abe Y, et al. TSHR mutations as a cause of congenital hypothyroidism in Japan: a population-based genetic epidemiology study. J Clin Endocrinol Metab. 2009;94(4):1317-1323. doi: 10.1210/jc.2008-1767.
16.Al Taji E, Biebermann H, Limanova Z, et al. Screening for mutations in transcription factors in a Czech cohort of 170 patients with congenital and early-onset hypothyroidism: identification of a novel PAX8 mutation in dominantly inherited early-onset non-autoimmune hypothyroidism. Eur J Endocrinol. 2007;156(5):521-529. doi: 10.1530/EJE-06-0709.
17.Bamforth JS, Hughes IA, Lazarus JH, et al. Congenital hypothyroidism, spiky hair, and cleft palate. J Med Genet. 1989;26(1):49-51. doi: 10.1136/jmg.26.1.49.
18.Cassio A, Nicoletti A, Rizzello A, et al. Current loss-of-function mutations in the thyrotropin receptor gene: when to investigate, clinical effects, and treatment. J Clin Res Pediatr Endocrinol. 2013;5 Suppl 1:29-39. doi: 10.4274/jcrpe.864.
19.Plachov D, Chowdhury K, Walther C, et al. PAX8, a murine paired box gene expressed in the developing excretory system and thyroid gland. Development. 1990;110(2):643-651.
20.de Sanctis L, Corrias A, Romagnolo D, et al. Familial PAX8 small deletion (c.989_992delACCC) associated with extreme phenotype variability. J Clin Endocrinol Metab. 2004;89(11):5669-5674. doi: 10.1210/jc.2004-0398.
21.Bamforth JS, Hughes IA, Lazarus JH, et al. Congenital hypothyroidism, spiky hair, and cleft palate. J Med Genet. 1989;26(1):49-51. doi: 10.1136/jmg.26.1.49.
22.Clifton-Bligh RJ, Wentworth JM, Heinz P, et al. Mutation of the gene encoding human TTF-2 associated with thyroid agenesis, cleft palate and choanal atresia. Nat Genet. 1998;19(4):399-401. doi: 10.1038/1294.
23.Stenson PD, Mort M, Ball EV, et al. The Human Gene Mutation Database: towards a comprehensive repository of inherited mutation data for medical research, genetic diagnosis and next-generation sequencing studies. Hum Genet. 2017;136(6):665-677. doi: 10.1007/s00439-017-1779-6.
24.Lek M, Karczewski KJ, Minikel EV, et al. Analysis of protein-coding genetic variation in 60,706 humans. Nature. 2016;536(7616): 285-291. doi: 10.1038/nature19057.

Study of molecular basis of thyroid dysgenesis

Congenital hypothyroidism is a heterogeneous group of diseases, which is manifested by loss of function of the thyroid gland that affects infants from birth. 80-85% of cases are due to different types of thyroid dysgenesis. 5 genes have been described that are involved in the pathogenesis of thyroid dysgenesis: i>TSHR, PAX8, FOXE1, NKX2-1, NKX2-5/i>. Aims. To evaluate the prevalence of mutations in the genes i>TSHR, PAX8, FOXE1, NKX2-1, NKX2-5/i> among patients with severe congenital hypothyroidism. Materials and methods. 161 patients (64 boys, 97 girls) with congenital hypothyroidism (TSH levels at neonatal screening or retesting greater than 90 mU/l) were included in the study. 138 subjects had different variants of thyroid dysgenesis, and 23 patients had normal volume of the gland. A next generation sequencing was used for molecular-genetic analysis. Sequencing was performed using PGM semiconductor sequencer (Ion Torrent, Life Technologies, USA) and a panel “Hypothyroidism” (Custom DNA Panel). Assessment of the pathogenicity of sequence variants were carried out according to the latest international guidelines (ACMG, 2015). Results. 13 patients had variants in thyroid dysgenesis genes (8,1%, 13/161): i>TSHR/i>, i>n/i> = 6; i>NKX2-1/i>, i>n/i> = 3; i>NKX2-5/i>, i>n/i> = 1; i>PAX8/i>, i>n/i> = 3; i>FOXE1/i>, i>n/i> = 0. Conclusions. Mutations in thyroid dysgenesis genes are a rare pathology. The majority of variants among our patients were identified in i>TSHR/i>.

Keywords:
дисгенезия, высокопроизводительное параллельное секвенирование, врожденный гипотиреоз, thyroid dysgenesis, next generation sequencing, congenital hypothyroidism