Abstract
Individuals with uniparental disomy of chromosome 14 (Temple and Kagami–Ogata syndromes) exhibit a number of developmental abnormalities originating, in part, from aberrant developmental expression of imprinted genes in the DLK1–DIO3 cluster. Although genomic imprinting has been reported in humans for some genes in the cluster, little evidence is available about the imprinting status of DIO3, which modulates developmental exposure to thyroid hormones. We used pyrosequencing to evaluate allelic expression of DLK1 and DIO3 in cDNAs prepared from neonatal foreskins carrying single-nucleotide polymorphisms (SNPs) in the exonic sequence of those genes, and hot-stop PCR to quantify DIO3 allelic expression in cDNA obtained from a skin specimen collected from an adult individual with known parental origin of the DIO3 SNP. In neonatal skin, DLK1 and DIO3 both exhibited a high degree of monoallelic expression from the paternal allele. In the adult skin sample, the allele preferentially expressed is that inherited from the mother, although a different, larger DIO3 mRNA transcript appears the most abundant at this stage. We conclude that DIO3 is an imprinted gene in humans, suggesting that alterations in thyroid hormone exposure during development may partly contribute to the phenotypes associated with uniparental disomy of chromosome 14.
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References
Reik W, Walter J : Genomic imprinting: parental influence on the genome. Nat Rev Genet 2001; 2: 21–32.
Kelsey G : The hows and whys of imprinting. Trends Genet 2000; 16: 15–16.
Knoll JH, Nicholls RD, Magenis RE, Graham Jr JM, Lalande M, Latt SA : Angelman and Prader-Willi syndromes share a common chromosome 15 deletion but differ in the parental origin of the deletion. Am J Med Genet 1989; 32: 285–290.
Maher ER, Reik W : Beckwith-Wiedemann syndrome: imprinting in clusters revisited. J Clin Invest 2000; 105: 247–252.
Preece MA, Moore GE : Genomic imprinting, uniparental disomy and foetal growth. Trends Endocrinol Metab 2000; 11: 270–275.
Wylie AA, Murphy SK, Orton TC, Jirtle RL : Novel imprinted DLK1/GTL2 domain on human chromosome 14 contains motifs that mimic those implicated in IGF2/H19 regulation. Genome Res 2000; 10: 1711–1718.
Buiting K, Kanber D, Martin-Subero JI et al: Clinical features of maternal uniparental disomy 14 in patients with an epimutation and a deletion of the imprinted DLK1/GTL2 gene cluster. Hum Mutat 2008; 29: 1141–1146.
Cotter PD, Kaffe S, McCurdy LD, Jhaveri M, Willner JP, Hirschhorn K : Paternal uniparental disomy for chromosome 14: a case report and review. [Review] [27 refs]. Am J Med Genet 1997; 70: 74–79.
Hosoki K, Kagami M, Tanaka T et al: Maternal uniparental disomy 14 syndrome demonstrates prader-willi syndrome-like phenotype. J Pediatr 2009; 155: 900–903e1.
Tsai CE, Lin SP, Ito M, Takagi N, Takada S, Ferguson-Smith AC : Genomic Imprinting contributes to thyroid hormone metabolism in the mouse embryo. Curr Biol 2002; 12: 1221–1226.
Hernandez A, Fiering S, Martinez E, Galton VA, St Germain D : The gene locus encoding iodothyronine deiodinase type 3 (Dio3) is imprinted in the fetus and expresses antisense transcripts. Endocrinology 2002; 143: 4483–4486.
Lin SP, Coan P, da Rocha ST et al: Differential regulation of imprinting in the murine embryo and placenta by the Dlk1-Dio3 imprinting control region. Development 2007; 134: 417–426.
Uejima H, Lee MP, Cui H, Feinberg AP : Hot-stop PCR: a simple and general assay for linear quantitation of allele ratios. [erratum appears in Nat Genet 2001;28(1):97]. Nat Genet 2000; 25: 375–376.
Dentice M, Luongo C, Huang S et al: Sonic hedgehog-induced type 3 deiodinase blocks thyroid hormone action enhancing proliferation of normal and malignant keratinocytes. Proc Natl Acad Sci USA 2007; 104: 14466–14471.
Sittig LJ, Herzing LB, Shukla PK, Redei EE : Parent-of-origin allelic contributions to deiodinase-3 expression elicit localized hyperthyroid milieu in the hippocampus. Mol Psychiatry 2011; 16: 786–787.
Tu HM, Legradi G, Bartha T, Salvatore D, Lechan R, Larsen PR : Regional expression of the type 3 iodothyronine deiodinase messenger ribonucleic acid in the rat central nervous system and its regulation by thyroid hormone. Endocrinology 1999; 140: 784–790.
Hernandez A, Martinez E, Croteau W St, Germain D : Complex organization and structure of sense and antisense transcripts expressed from the DIO3 gene imprinted locus. Genomics 2004; 83: 413–424.
Hayward BE, Kamiya M, Strain L et al: The human GNAS1 gene is imprinted and encodes distinct paternally and biallelically expressed G proteins. Proc Natl Acad Sci USA 1998; 95: 10038–10043.
Wroe SF, Kelsey G, Skinner JA et al: An imprinted transcript, antisense to Nesp, adds complexity to the cluster of imprinted genes at the mouse Gnas locus. Proc Natl Acad Sci USA 2000; 97: 3342–3346.
Arnaud P, Monk D, Hitchins M et al: Conserved methylation imprints in the human and mouse GRB10 genes with divergent allelic expression suggests differential reading of the same mark. Hum Mol Genet 2003; 12: 1005–1019.
Martinez ME, Charalambous M, Saferali A et al: Genomic imprinting variations in the mouse type 3 deiodinase gene between tissues and brain regions. Mol Endocrinol 2014; 28: 1875–1886.
Kagami M, Matsuoka K, Nagai T et al: Paternal uniparental disomy 14 and related disorders: placental gene expression analyses and histological examinations. Epigenetics 2012; 7: 1142–1150.
Huang SA, Dorfman DM, Genest DR, Salvatore D, Larsen PR : Type 3 iodothyronine deiodinase is highly expressed in the human uteroplacental unit and in fetal epithelium. J Clin Endocrinol Metab 2003; 88: 1384–1388.
Ueta CB, Oskouei BN, Olivares EL et al: Absence of myocardial thyroid hormone inactivating deiodinase results in restrictive cardiomyopathy in mice. Mol Endocrinol 2012; 26: 809–818.
Acknowledgements
We are grateful to Donald St Germain for critical reading of the manuscript and to R. Calvo, D. Collison, D. Burris and I. Emery for assistance with the collection of the samples. This study was partially supported by the MMC BioBank, a core facility of Maine Medical Center Research Institute, and by grants from the National Institutes of Mental Health and Diabetes, Digestive and Kidney Diseases (MH083220, DK095908 and MH096050). In this work, we used the facilities of the Protein, Nucleic Acid and Cell Imaging Core at Maine Medical Center Research Institute, supported by NIH grant P30 GM103392.
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Martinez, M., Cox, D., Youth, B. et al. Genomic imprinting of DIO3, a candidate gene for the syndrome associated with human uniparental disomy of chromosome 14. Eur J Hum Genet 24, 1617–1621 (2016). https://doi.org/10.1038/ejhg.2016.66
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DOI: https://doi.org/10.1038/ejhg.2016.66
