Dataset Information

Public Cohort Analysis Identifies Thyroglobulin Variants as Hypothyroidism Risk Factors

ABSTRACT: Hypothyroidism is a prevalent endocrine disorder that is characterized by the insufficient production of thyroid hormones (T3/T4), with etiologies related to environmental, autoimmune factors, or genetic variants. Thyroglobulin (Tg) serves as the prohormone to T3/T4 production and due to a large genetic diversity there are many variants of clinical uncertainty. Here, we leveraged the large-scale “All of Us” biobank to investigate disease association of Tg variants that are more prevalent in the general population compared to previously characterized variants. We compared these variants to thyroid stimulating hormone levels and levothyroxine (LT4) usage to estimate thyroid function. This identified R152H, Q870H, A993T, P1012L and P1494L variants linked to an increased susceptibility to levothyroxine usage and decreased thyroid function while the R320C variant was associated with a decrease in thyroid function. Molecular characterization and secretion of these variants in Fisher rat thyroid cells showed decreased secretion efficiency and/or correlates with higher anti-TPO antibody levels in participants for disease associated variants while benign variants showed minimal effect. Using previously determined structures of Tg, variants found with a decrease in thyroid efficiency are in structural positions that disrupt stabilizing bonds, but variants with minimal effect are in more flexible regions with fewer interactions. Affinity purification mass spectrometry demonstrated that secretion deficient variants show higher engagement with the protein homeostasis network. We estimate that around 150,000 individuals in the US could benefit from precision medicine with the variants highlighted in this study currently take levothyroxine, with ~100,000 of those individuals carrying the Q870H variant. Our findings highlight the power of combining data from large public biobanks with molecular characterization to better understand the genotype to phenotype relationships of Tg. Our analysis suggests that Q870H serves as a possible candidate to be targeted by molecular therapies to restore secretion and T3/T4 production offering a precision medicine approach beyond LT4 replacement therapy.

INSTRUMENT(S):

ORGANISM(S): Rattus Norvegicus (rat) Homo Sapiens (human)

TISSUE(S): Cell Culture

SUBMITTER: Jake Hermanson

LAB HEAD: Lars Plate

PROVIDER: PXD069688 | Pride | 2026-08-07

REPOSITORIES: Pride

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			Action	DRS
	Exp-M-026_AoU_16plex.mzTab	Mztab
	Exp-M-026_AoU_16plex_100C_Rep1.raw	Raw
	Exp-M-026_AoU_16plex_100C_Rep2.raw	Raw
	Exp-M-026_AoU_16plex_100C_Rep3.raw	Raw
	Exp-M-026_AoU_16plex_100C_Rep4.raw	Raw

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Publications

Public Cohort Analysis Identifies Thyroglobulin Variants as Hypothyroidism Risk Factors.

Hermanson Jake N JN Hudson Andrew D AD Plate Lars L

The Journal of biological chemistry 20260716

Hypothyroidism is a prevalent endocrine disorder characterized by insufficient thyroid hormone (T3T4) production. Thyroglobulin (Tg) serves as the prohormone for T3 and T4 production, with many variants of uncertain clinical significance due to genetic diversity in the Tg gene. We leveraged the large-scale All of Us biobank to investigate the disease association of prevalent yet undercharacterized Tg variants. We related variant presence to thyroid-stimulating hormone levels and levothyroxine (L ...[more]

PMID: 42463052

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Project description:Background: Thyroxine (T4) is generally considered to be a pro-hormone that requires conversion to 3,5,3’-triiodothyronine (T3) to exert biological activity. Although evidence suggests that T4 has intrinsic activity, it is questionable if this activity has any physiological relevance. Methods: To answer this question, triple KO mice (Triples) that cannot express the types 1 (D1) and 2 (D2) deiodinase and the Pax8 genes were generated. Thus they lack a thyroid and cannot convert T4 to T3. Triples were injected on alternate days with either vehicle or physiological doses of T4, T3 or T3+T4 from postnatal days 2 to 14. They were euthanized at P15 and RNA-seq was employed to profile gene expression in liver. In another experiment, Pax8KO mice were injected with T3, T4 or T4 +T3, and growth rate and survival to P84 were determined. Results: The growth retardation of Triples was not improved by either T3 or T4 alone but was significantly improved by T4+T3. In liver, T4 significantly regulated the expression of genes that were also regulated by T3, but the proportion of genes that were negatively regulated was higher in mice treated with T4 than with T3. Treatment with T4+T3 identified genes that were regulated synergistically by T3 and T4, and genes that were regulated only by T4+T3. Analysis of these genes revealed enrichment in mechanisms related to cell proliferation and cholesterol physiology, suggesting a unique contribution of T4 to these biological functions. Pax8KO mice all survived to P84 when injected with T4 or T4+T3 but survival rate with T3 was 50% and 10% at 3.5 and 12 weeks of life, respectively. Conclusion: T4 has intrinsic activity in vivo and is critical for survival and growth. At a physiological level, T4 per se can up- or down-regulate many T3 target genes in the neonatal liver. While most of these genes are also regulated by T3, subsets respond exclusively to T4 or demonstrate enhanced or normalized expression only in the presence of both hormones. These studies demonstrate for the first time a complex dependency on both T4 and T3 for normal mammalian growth and development.

Project description:A spontaneous mutation in the Taconic Biosciences wildtype C57BL/6NTac mouse was discovered that is associated with early-onset histopathologic sequalae typical of thyroid dysplasia. The spontaneous mutation resulted from insertion of a L1 long interspersed nuclear element (LINE-1) into an intron within the Thyroglobulin (Tg) gene. The mouse genome contains a significant amount of retrotransposon DNA, and these mobile genetic elements routinely change genomic location through retrotransposition, including in germ cells. Analysis of the thyroid transcriptome suggested that the presence of the LINE-1 interferes with the Tg gene splicing, resulting in exclusion of exon 26 from most Tg transcripts in animals homozygous for the insertion. The LINE-1 insertion allele of the Tg gene has been designated Tgtdys-Tac. The resulting phenotype is inherited in an autosomal dominant manner with affected mice exhibiting thyroid follicular cell dysplasia that progresses to thyroid adenoma by 9 months of age with complete penetrance in homozygotes. Serum thyroid hormone measurements revealed a decrease in triiodothyronine (T3) levels in homozygotes at 9 months and 12 months of age, as well as a decrease in tetraiodothyronine (T4) levels at 6-9 months in homozygotes and at 12 months of age in both heterozygotes and homozygotes. In addition, serum Thyroid Stimulating Hormone (TSH) level was strongly increased in homozygotes at 6-8 months of age, consistent with hypothyroidism. Computational molecular modeling showed that omission of the 61 amino acids from the TG protein arm domain, which is the consequence of exon 26-skipping in the Tg transcript, results in decreased local stability. This result in combination with the observed up-regulation in unfolded protein response pathways in the thyroids of affected animals, identifies the arm domain of TG as important for its proper cellular distribution. This report describes a spontaneous retrotransposon insertion causatively linked to dysregulated physiological phenotypes in a widely used inbred mouse strain.