Thyroglobulin gene mutations in Chinese patients with congenital hypothyroidism
Introduction
Congenital hypothyroidism, with its incidence of 1/2000 to 1/4000 in newborns (Agretti et al., 2013), is caused either by thyroid gland development disorders, which accounts for 85% of cases, or by thyroid hormone synthesis defects, which accounts for the remaining 15% of cases (Park and Chatterjee, 2005).
The human thyroglobulin (TG) gene is a relatively large gene spanning a 270-kb region on chromosome 8q24 (Mendive et al., 2001), consisting of 48 exons. The thyroglobulin monomer encloses three regions with repeat domains and one acetylcholinesterase-homology domain (ACHE-like domain). Region I comprises 10 TG type-1 repeats, a linker and hinge segments. Region II contains 3 TG type-2 repeats and the 11th TG type-1 repeat. Region III contains five TG type-3 repeats. The ACHE-like domain may function as an intramolecular chaperone and a molecular escort (Lee and Arvan, 2011, Lee et al., 2008). Thyroglobulin, a homodimeric glycoprotein of 660 kDa, is the most abundant expressed protein in the thyroid gland, acting as a matrix for thyroid hormone synthesis as well as a storage for inactive thyroid hormones and iodide (Lamas et al., 1989).
Since the first TG mutation described in 1991 (Ieiri et al., 1991), over 70 mutations were reported to be related with goiter or hypothyroidism and recorded in the HGMD professional 2015.1 (www.hgmd.cf.ac.uk/ac/index.php), including 50 missense/nonsense mutations, 13 splicing mutations, 1 regulatory mutations, 10 small deletions, 3 small insertions, 1 gross deletions and 1 complex mutation. Thyroid dyshormonogenesis due to TG gene mutations have an estimated incidence of approximately from 1:71,000 to 1:100,000 (Kanou et al., 2007, Narumi et al., 2011, van de Graaf et al., 1999a, van de Graaf et al., 1999b; Targovnik et al., 2010).
CH is relatively more common in Chinese population (Maitusong et al., 2012, Shi et al., 2012, Gu et al., 2008), but the TG mutation and its frequency in Chinese patient population is currently unknown. Here we conducted a TG gene mutation screening among a cohort of CH patients from Guangxi Zhuang Autonomous Region, China.
Section snippets
Subjects
Patients involved in this study were enrolled from the Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region, China, and were initially identified by newborn screening for CH among 1,238,340 newborns. Of all CH patients with elevated TSH levels (TSH ≥ 8.35 μIU/mL) and decreased FT4 level (FT4<12.3 ρmol/L), 382 were selected for the following sequencing and analysis. In addition, a cohort of 600 local subjects with normal TSH and FT4 levels was enrolled as a normal control. The
Variants detection
22 rare and potentially functional variants were resulted after removing 22 common or low-impact variants. Among these, eight are novel variants and 14 variants had been previously reported in HGMD, dbSNP or ExAC (Table 1, Table 2, Table 3, Fig. 1). It is notable that most of the variants were present as heterozygous in patients. Four variants were homozygous in 8 patients: 1) c.274+2T>G was found in four patients, 2) c.3035C>T was found in one patient, 3) c.6391delTTGT was found in one
Discussion
This is the first mutation screening study for TG gene in Chinese CH patients. We identified 22 rare and potentially high-impact variants, eight were novel. Ten CH patients had biallelic variants in TG gene, mostly with reduced TG level due to null pathogenic variants. At least seven patients showed very low TG level, their CH are believed to be due to the biallelic TG pathogenic variants. Given the fact that we identified 668 CH patients from 1,238,340 newborns and 7 out of 382 CH patients we
Acknowledgments
We thank all members of the research group for their contributions to this investigation. We thank the National Natural Science Foundation of China (81260126, 81201353), Key Projects of Guangxi Health Department (2012025) and Guangxi Natural Science Foundation Program (2012GXNSFAA053174) for financial support.
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Cited by (22)
Curating the gnomAD database: Report of novel variants in the thyrogobulin gene using in silico bioinformatics algorithms: Computational analysis of TG variants
2021, Molecular and Cellular EndocrinologyCitation Excerpt :Variants located in positions 1 and 2 to 3′ or 5′ of each exon and classified as likely pathogenic by our algorithm were reclassified as pathogenic according to our sorting following the ACMG recommendations. Our results showed that the splice site prediction tools were highly efficient in evaluating and confirming the pathogenicity of all variants analyzed and they are strongly consistent with previous clinical, biochemical, and molecular evaluations (Abdul-Hassan et al., 2013; Alzahrani et al., 2006; Bruellman et al., 2020b; Chen et al., 2018; Citterio et al., 2015; de Filippis et al., 2017; Fu et al., 2016b; Gutnisky et al., 2004; Hermanns et al., 2013; Hishinuma et al., 2006; Hu et al., 2016; Ieiri et al., 1991; Lo et al., 2018; Makretskaya et al., 2018; Medeiros-Neto et al., 1996; Narumi et al., 2011; Nicholas et al., 2016; Niu et al., 2009; Pardo et al., 2008, 2009; Peteiro-Gonzalez et al., 2010; Pio et al., 2021; Rubio et al., 2008; Stoupa et al., 2021; Targovnik et al., 1995, 2001, 2012; Watanabe et al., 2019; Zou et al., 2018). The distribution of the 53 gnomAD variants located at the 3′ splice site was as follows: 10 at position −5, 13 at −4, 14 at −3, 9 at −2 and 6 at −1, and a large deletion involving the 3′ splice site, c.8189-10_8196delTCTGTTTCAGATGGAGCC, whereas the 64 gnomAD variants located at the 5′ splice site was as follows: 26 at position +1, 8 at +2, 10 at +3, 8 at +4 and 12 + 5.
Structure and genetic variants of thyroglobulin: Pathophysiological implications
2021, Molecular and Cellular EndocrinologyCitation Excerpt :The loss of the tyrosine149 provides a coherent explanation to the hypothyroid status of the patient (Ieri et al., 1991). To date, two hundred and twenty-nine variants in the human TG gene have been identified: 28 splice site variants (8 in the acceptor splice site and 20 in the donor splice site), 42 nonsense variants, 130 missense variants (18 located in the wild type cysteine residues, 7 originating new cysteine residues, 28 in the ChEL-homology domain and 77 located along the remaining TG monomer), 5 duplications (4 singles and 1 multiple), 2 insertion (1 multiple and 1 involving a large number of nucleotides), 21 deletions (13 singles, 4 multiples and 4 involving a large number of nucleotides) and 1 imperfect DNA inversion (Table 1) (Abdul-Hassan et al., 2013; Agretti et al., 2013; Alzahrani et al., 2006; Baryshev et al., 2004; Bruellman et al., 2020a, 2020b; Brust et al., 2011; Cangul et al., 2014; Caputo et al., 2007a, 2007b; Caron et al., 2003; Chen et al., 2018; Citterio et al., 2011, 2013a, 2013b, 2015; Corral et al., 1993; de Filippis et al., 2017; Fan et al., 2017; Fu et al., 2016a, 2016b; Gonzáles-Sarmiento et al., 2001; Gutnisky et al., 2004; Heo et al., 2019; Hermanns et al., 2013; Hishinuma et al., 1999, 2005, 2006; Hu et al., 2016; Ieiri et al., 1991; Jiang et al., 2016; Kahara et al., 2012; Kanou et al., 2007; Kim et al., 2008; Kitanaka et al., 2006; Liu et al., 2012; Lo et al., 2018; Löf et al., 2016; Long et al., 2018; Machiavelli et al., 2010; Makretskaya et al., 2018; Medeiros-Neto et al., 1996; Mendive et al., 2005; Mittal et al., 2016; Mizokami et al., 2019; Moya et al., 2011; Narumi et al., 2011; Nicholas et al., 2016; Niu et al., 2009; Pardo et al., 2008, 2009; Pérez-Centeno et al., 1996; Peteiro-Gonzalez et al., 2010; Pio et al., 2021; Raef et al., 2010; Rivolta et al., 2005; Rubio et al., 2008; Santos-Silva et al., 2019; Siffo et al., 2018; Sun et al., 2018; Tanaka et al., 2020; Targovnik et al., 1993, 1995, 2001, 2010b, 2012; van de Graaf et al., 1999b; Wang et al., 2020; Watanabe et al., 2018, 2019, Wright et al., 2021; Yamaguchi et al., 2020; Yoon et al., 2020; Yu et al., 2018; Zou et al., 2018). p.Cys1077Arg and p.Cys1996Ser (originally published as p.Cys1995Ser) mutations are the most frequently identified TG variants in Japanese population (Table 1), whereas the most frequent mutation found in Caucasian populations is p.Arg296* (originally published as p.Arg277*) (Table 1).
A novel mutation in intron 11 donor splice site, responsible of a rare genotype in thyroglobulin gene by altering the pre-mRNA splincing process. Cell expression and bioinformatic analysis
2021, Molecular and Cellular EndocrinologyCitation Excerpt :The clinical spectrum ranges from euthyroid to mild or severe hypothyroidism. During the last decades, two hundred twenty-seven variants in the human TG gene have been reported associated with congenital goiter and also endemic and nonendemic goiter: 26 splice site variants (19 in the donor splice site and 7 in the acceptor splice site), 42 nonsense variants, 130 missense variants (18 located at in the wild type cysteine residues, 7 originating new cysteine residues, 27 in the ChEL-homology domain and 78 located along the remaining TG monomer), 5 duplications (4 singles and 1 multiple), 2 insertion (1 multiple and 1 involving a large number of nucleotides), 21 deletions (13 singles, 4 multiples and 4 involving a large number of nucleotides) and 1 imperfect DNA inversion [Abdul-Hassan et al., 2013; Agretti et al., 2013; Alzahrani et al., 2006; Baryshev et al., 2004; Bruellman et al., 2020a, 2020b; Brust et al., 2011; Cangul et al., 2014; Caputo et al., 2007a, 2007b; Caron et al., 2003; Chen et al., 2018; Citterio et al., 2011, 2013a, 2013b, 2015; Corral et al., 1993; de Filippis et al., 2017; Fan et al., 2017; Fu et al., 2016b,a; González-Sarmiento et al., 2001; Gutnisky et al., 2004; Heo et al., 2019; Hermanns et al., 2013; Hishinuma et al., 1999, 2005, 2006; Hu et al., 2016; Ieiri et al., 1991; Jiang et al., 2016; Kahara et al., 2012; Kanou et al., 2007; Kim et al., 2008; Kitanaka et al., 2006; Liu et al., 2012; Lof et al., 2016; Long et al., 2018; Machiavelli et al., 2010; Makretskaya et al., 2018; Medeiros-Neto et al., 1996; Mendive et al., 2005; Mittal et al., 2016; Mizokami et al., 2019; Moya et al., 2011; Narumi et al., 2011; Nicholas et al., 2016; Niu et al., 2009; Pardo et al., 2008, 2009; Pérez-Centeno et al., 1996; Peteiro-Gonzalez et al., 2010; Raef et al., 2010; Rivolta et al., 2005; Rubio et al., 2008; Santos-Silva et al., 2019; Siffo et al., 2018; Sun et al., 2018; Tanaka et al., 2020; Targovnik et al., 1993, 1995, 2001, 2010b, 2012; van de Graaf et al., 1999; Wang et al., 2020; Watanabe et al., 2018, 2019, Wright et al., 2020; Yamaguchi et al., 2020; Yu et al., 2018; Zou et al., 2018]. The patients are typically homozygous or compound heterozygous for the gene mutations, and their parents are carriers of one of such variant.
p.L571P in the linker domain of rat thyroglobulin causes intracellular retention
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2020, Molecular and Cellular EndocrinologyMolecular analysis of thyroglobulin mutations found in patients with goiter and hypothyroidism
2018, Molecular and Cellular Endocrinology