TG – Familial Thyroid Dyshormonogenesis

Thyroglobulin (TG) functions as the precursor matrix for thyroid hormone synthesis and is essential for iodotyrosine coupling in the follicular lumen. Familial thyroid dyshormonogenesis (MONDO:0010132) is characterized by autosomal recessive goitrous congenital hypothyroidism resulting from impaired TG folding, secretion, and hormonogenesis. Both homozygous and compound heterozygous TG variants have been reported in consanguineous and nonconsanguineous pedigrees worldwide. Patients present with a spectrum ranging from mild enlargement with compensated euthyroidism to severe hypothyroidism requiring full levothyroxine replacement. Serum thyroglobulin is typically undetectable or markedly reduced, guiding targeted genetic testing. The inheritance mode is clearly autosomal recessive, with consistent segregation of biallelic pathogenic alleles in affected siblings.

Genetic evidence includes over 50 unrelated probands across more than 20 families (PMID:38373250, PMID:29275168). Segregation analysis demonstrates complete cosegregation of candidate TG variants in affected siblings and compound heterozygotes. Major cohorts include 30 patients from a Japanese newborn screening study (PMID:38373250), 8 European cases of goitrous hypothyroidism (PMID:29275168), and 6 patients from a multicentre analysis of congenital goiter (PMID:19438905). Biallelic loss-of-function alleles such as p.Arg296Ter and the splice donor c.638+1G>A are consistently associated with severe phenotypes. Control datasets show absence of these alleles in healthy populations, reinforcing pathogenicity.

The variant spectrum exceeds 100 deleterious TG alleles, including nonsense, frameshift, splice-site, and missense changes. Truncating mutations cluster in exons encoding the acetylcholinesterase-like (ChEL) domain, abrogating dimerization and secretion. Missense variants frequently affect conserved cysteines or inter-domain interfaces, causing misfolding and ER retention. The recurrent splice-site mutation c.638+1G>A induces exon skipping and a premature stop, observed in multiple unrelated cases. Founder effects are not evident; independent haplotypes support recurrent mutational events. Carrier frequency in population databases is <0.001 for known pathogenic variants.

Functional studies demonstrate that TG variants impair intracellular folding and trafficking, leading to retention in the endoplasmic reticulum and rapid degradation. Endo H sensitivity assays and immunohistochemistry confirm failure of mutant TG to reach the Golgi (PMID:9790265). Chimeric constructs replacing the ChEL domain with acetylcholinesterase rescue TG secretion, highlighting the domain’s essential dimerization role (PMID:14764582). Ex vivo splicing assays validate aberrant mRNA processing for splice-site variants. ER stress markers and defective hormone release in patient thyrocytes link molecular dysfunction to clinical hypothyroidism. Collectively, mechanistic data establish haploinsufficiency as the primary pathogenic mechanism.

No significant conflicting evidence has emerged to refute the TG–dyshormonogenesis association. Variable expressivity of missense alleles aligns with a phenotypic continuum rather than alternative diagnoses. Genome-wide data have not implicated TG in other thyroid disorders at a genome-wide significance level. Functional SNPs in other dyshormonogenesis genes (e.g., DUOX2 p.His678Arg) illustrate broader etiologies without disputing TG’s causality. Overall, evidence is consistent, reproducible, and robust across diverse cohorts and experimental platforms.

In conclusion, autosomal recessive TG variants are a definitive cause of familial thyroid dyshormonogenesis. Genetic testing for TG should be prioritized in patients with congenital goiter and low serum thyroglobulin, regardless of gland size. Identification of biallelic loss-of-function variants informs prognosis and guides lifelong levothyroxine therapy. In vitro functional assays support variant interpretation in diagnostic laboratories. Future studies on genotype–phenotype correlations for missense alleles will refine clinical management. Key take-home: TG genetic testing provides a definitive diagnosis for familial thyroid dyshormonogenesis, enabling tailored patient care.

References

• The Journal of clinical endocrinology and metabolism • 2006 • Clinical case seminar: metastatic follicular thyroid carcinoma arising from congenital goiter as a result of a novel splice donor site mutation in the thyroglobulin gene. PMID:16403815
• Clinical Endocrinology • 2010 • Molecular analysis of congenital goitres with hypothyroidism caused by defective thyroglobulin synthesis. Identification of a novel c.7006C>T [p.R2317X] mutation and expression of minigenes containing nonsense mutations in exon 7. PMID:19438905
• Clinical Endocrinology • 2007 • Congenital hypothyroidism with goitre caused by new mutations in the thyroglobulin gene. PMID:17532758
• Molecular and Cellular Endocrinology • 2018 • Molecular analysis of thyroglobulin mutations found in patients with goiter and hypothyroidism. PMID:29275168
• The Journal of clinical endocrinology and metabolism • 2024 • Genotype-Phenotype Correlations in 30 Japanese Patients With Congenital Hypothyroidism Attributable to TG Defects. PMID:38373250
• Endocrine Journal • 1998 • Missense mutation (C1263R) in the thyroglobulin gene causes congenital goiter with mild hypothyroidism by impaired intracellular transport. PMID:9790265
• The Journal of Biological Chemistry • 2004 • The acetylcholinesterase homology region is essential for normal conformational maturation and secretion of thyroglobulin. PMID:14764582

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