Ann Pediatr Endocrinol Metab.  2024 Oct;29(5):279-283. 10.6065/apem.2448186.093.

Deciphering the mystery of CHNG3

• Narumi S

• KMID: 2560463
• DOI: http://doi.org/10.6065/apem.2448186.093

Abstract

Congenital hypothyroidism (CH), characterized by insufficient thyroid hormone production due to abnormalities in the hypothalamic-pituitary-thyroid axis, is the most common congenital endocrine disorder. We previously conducted comprehensive genetic screening of 102 patients with permanent CH born in Kanagawa Prefecture, Japan and identified mutations in several genes in 19 CH patients, including defects in genes encoding dual oxidase 2, thyroglobulin, thyrotropin receptor, thyroid peroxidase, and paired-box 8. Despite these findings, approximately 80% of cases remain unexplained. CH pedigrees unexplained by known genetic forms of CH have been reported in the literature and registered as congenital hypothyroidism, nongoitrous, 3 (CHNG3; %609893) in Online Mendelian Inheritance in Man. We also identified a Japanese pedigree of CH that was compatible with CHNG3. However, the exact genetic cause of CHNG3 was not revealed by standard analysis methods such as exome sequencing and array comparative genomic hybridization. We therefore took a combined approach and analyzed a total of 11 undiagnosed CH pedigrees by whole genome sequencing to analyze a 3-Mb linkage region, and found a disease-causing variant affecting a TTTG microsatellite in a noncoding region on chromosome 15. Further analysis revealed that 13.9% of 989 Japanese CH patients had abnormalities involving the TTTG microsatellite, with a substantial proportion (41.5%) of familial CH cases carrying these mutations. Identification of the genetic cause of CHNG3 provides new insights into the pathogenesis of CH, and highlights the need for continued exploration of noncoding genomic regions in Mendelian disorders of unknown etiology.

Keyword

Congenital hypothyroidism; Genetics; Whole genome sequencing; Genetic linkage

Figure

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  Fig. 1. Physiological roles of the causative genes of Mendelian congenital hypothyroidism in thyroid cells. One thyroid cell is drawn in the figure, with the vascular lumen at the bottom and the follicular lumen at the top. Inorganic iodine (I-) that reaches the thyroid gland via the blood stream is concentrated in thyroid cells by the action of sodium-iodine symporter (SLC5A5) and then pumped into the thyroid follicles by the action of SLC26A family transporters (SLC26A4 and SLC26A7). Thyroid follicles contain large amounts of thyroglobulin (TG), a macroprotein synthesized by thyroid cells. Thyroid peroxidase (TPO) catalyzes (i) the addition of inorganic iodine to several tyrosine residues of TG and (ii) a coupling reaction that creates a triiodothyronine (T3) or thyroxine (T4) group from 2 iodinated tyrosine residues. DUOXA2 is an endoplasmic reticulum protein that promotes the maturation of DUOX2. DUOX2 provides the hydrogen peroxide required for the iodination reaction of TG by TPO. Iodinated TG is taken up into thyroid cells by endocytosis and undergoes proteolysis in lysosomes to release T3 and T4. The iodotyrosine that is not converted to T3 and T4 is deiodinated by the membrane enzyme iodotyrosine deiodinase (IYD), and the recovered inorganic iodine is reused for thyroid hormone synthesis. These thyroid hormone synthesis pathways are positively regulated by the TSH-TSH receptor pathway. In addition, thyroid-specific transcription factors PAX8, NKX2-1, and FOXE1 regulate the expression levels of these thyroid hormone synthesis-related molecules. TSH, thyroid-stimulating hormone; TSHR, TSH receptor.

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  Fig. 2. A Japanese large pedigree of congenital hypothyroidism of unknown etiology. In the figure, square symbols indicate males and round symbols indicate females. Arrows indicate the proband. Filled symbols indicate individuals with hypothyroidism.

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  Fig. 3. Percentage of Mendelian forms of congenital hypothyroidism (CH). Prior to the recognition of CHNG3 (shown in dark blue in the figure), there was no difference in the proportion of patients with Mendelian forms of CH, which was about 20% in the whole patient cohort (A) and in the subgroup with any family history (B). Today, about 1/3 of all patients and about 2/3 of patients with family history have known Mendelian forms of CH. TG, thyroglobulin; TPO, thyroid peroxidase; CHNG3, congenital hypothyroidism, nongoitrous, 3. Adapted from Narumi et al. Nat Genet 2024;56:869-876 [13].

Reference

References

1. Nagasaki K, Asami T, Ogawa Y, Kikuchi T, Uchiyama M. A study of the etiology of congenital hypothyroidism in the Niigata prefecture of Japan in patients born between 1989 and 2005 and evaluated at ages 5-19. Thyroid. 2011; 21:361–5.

2. Narumi S, Muroya K, Abe Y, Yasui M, Asakura Y, Adachi M, et al. TSHR mutations as a cause of congenital hypothyroidism in Japan: a population-based genetic epidemiology study. J Clin Endocrinol Metab. 2009; 94:1317–23.

3. Narumi S, Muroya K, Asakura Y, Aachi M, Hasegawa T. Molecular basis of thyroid dyshormonogenesis: genetic screening in population-based Japanese patients. J Clin Endocrinol Metab. 2011; 96:E1838–42.

4. Narumi S, Muroya K, Asakura Y, Adachi M, Hasegawa T. Transcription factor mutations and congenital hypothyroidism: systematic genetic screening of a populationbased cohort of Japanese patients. J Clin Endocrinol Metab. 2010; 95:1981–5.

5. Corbetta C, Weber G, Cortinovis F, Calebiro D, Passoni A, Vigone MC, et al. A 7-year experience with low blood TSH cutoff levels for neonatal screening reveals an unsuspected frequency of congenital hypothyroidism (CH). Clin Endocrinol (Oxf). 2009; 71:739–45.

6. Ng SB, Turner EH, Robertson PD, Flygare SD, Bigham AW, Lee C, et al. Targeted capture and massively parallel sequencing of 12 human exomes. Nature. 2009; 461:272–6.

7. Sun Y, Bak B, Schoenmakers N, van Trotsenburg AS, Oostdijk W, Voshol P, et al. Loss-of-function mutations in IGSF1 caus e an X-linked syndrome of central hypothyroidism and testicular enlargement. Nat Genet. 2012; 44:1375–81.

8. Zou M, Alzahrani AS, Al-Odaib A, Alqahtani MA, Babiker O, Al-Rijjal RA, et al. Molecular analysis of congenital hypothyroidism in Saudi Arabia: SLC26A7 mutation is a novel defect in thyroid dyshormonogenesis. J Clin Endocrinol Metab. 2018; 103:1889–98.

9. Cangul H, Liao XH, Schoenmakers E, Kero J, Barone S, Srichomkwun P, et al. Homozygous loss-of-function mutations in SLC26A7 cause goitrous congenital hypothyroidism. JCI Insight. 2018; 3:e99631.

10. Ishii J, Suzuki A, Kimura T, Tateyama M, Tanaka T, Yazawa T, et al. Congenital goitrous hypothyroidism is caused by dysfunction of the iodide transporter SLC26A7. Commun Biol. 2019; 2:270.

11. Grasberger H, Mimouni-Bloch A, Vantyghem MC, van Vliet G, Abramowicz M, Metzger DL, et al. Autosomal dominant resistance to thyrotropin as a distinct entity in five multigenerational kindreds: clinical characterization and exclusion of candidate loci. J Clin Endocrinol Metab. 2005; 90:4025–34.

12. Grasberger H, Vaxillaire M, Pannain S, Beck JC, MimouniBloch A, Vatin V, et al. Identification of a locus for nongoitrous congenital hypothyroidism on chromosome 15q25.3-26.1. Hum Genet. 2005; 118:348–55.

13. Narumi S, Nagasaki K, Kiriya M, Uehara E, Akiba K, Tanase-Nakao K, et al. Functional variants in a TTTG microsatellite on 15q26.1 cause familial nonautoimmune thyroid abnormalities. Nat Genet. 2024; 56:869–76.

14. Antonarakis SE, Krawczak M, Cooper DN. The nature and mechanisms of human gene mutation. In : Sriver CR, Beaudet AL, Sly WS, Valle D, editors. The metabolic and molecular bases of inherited disease. 7th Ed. New York: McGraw-Hill;1995. p. 259–91.