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Novel thyroid specific transcripts identified by SAGE: implication for congenital
hypothyroidism
Moreno Navarro, J.C.
Publication date
2003
Link to publication
Citation for published version (APA):
Moreno Navarro, J. C. (2003). Novel thyroid specific transcripts identified by SAGE:
implication for congenital hypothyroidism.
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Summary y
Summaryy in English
IdentificationIdentification of novel genes involved in congenital hypothyroidism.
AA paradigm of molecular medicine is the identification of functionally specialized geness in the search for defects responsible for human disease. The identification of tissue-specificc genes is essential to investigate the molecular background and the factorss involved in the patho-physiology of disease. In order to unravel the molecularr basis of congenital hypothyroidism we have pursued the identification of geness relevant to thyroid physiology, following a strategy based on the serial analysiss of gene expression (SAGE).
AA SAGE library was constructed from thyroid tissue containing more than 4.000 shortt sequence tags (10 base pairs) which represent formerly unidentified mRNA molecules.. A method was then developed to select a reduced number of interesting tagss preferentially expressed in thyroid. Using this in silico approach, three tags weree selected for further research.
Thee first tag corresponds to the recently identified THOX2 gene, involved in the generationn of H202 in the thyroid follicle, a critical step in the synthesis of thyroid
hormones.. Screening for mutations in the THOX2 gene was therefore performed in childrenn with "idiopathic" congenital hypothyroidism. Four inactivating mutations weree identified leading to a prematurely truncated THOX2 protein. One patient, with severee and permanent congenital hypothyroidism, had a inactivating mutation on bothh alleles of the THOX2 gene. Three other patients, in whom only one allele was mutated,, had moderate congenital hypothyroidism, associated with a partial iodide organificationn defect. Hypothyroidism in this latter patients showed a transient biochemicall expression, These findings show the crucial role of THOX2 in thyroidal H2022 production, since the biallelic inactivation of the THOX2 gene completely
disruptss thyroid hormone synthesis. They also represent the first evidence that geneticc defects are involved in transient forms of congenital hypothyroidism
Usingg the second tag. we cloned the DEHAL1 gene. This novel gene is highly expressedd in the thyroid but also present in liver, kidney and mammary gland. The mRNAA has 7.2 kb and is subject to alternative splicing. The encoded protein belongss to the family of nitroreductases, enzymes that use flavin mononucleotide as co-factor.. Recently we showed that the function of this protein is the dehalogenation
off lodotyrosines (mono-iodotyros.ne [MIT] and di-iodotyrosine [DIT]), the main lodinatedd side-products of the synthesis of thyroid hormones. This crucial activity ailowss the in-gland recycling of iodine for further hormonogenesis. Therefore,
DEHAL1DEHAL1 represents the best candidate gene for the human dehalogenase
deficiency,, a disorder that causes familial goitre and congenital hypothyroidism associatedd with abnormal losses of MIT and DIT in the urine.
Thee third tag corresponds to a novel transcript expressed in thyroid and endocrine cellss of stomach and lung. This gene, designated NM41. maps to human chromosomee 16q and encodes an mRNA of 1.4 kb. The predicted protein shows structurall homologies with the so called cystine-knot proteins, secreted molecules knownn to play a role in morphogenesis. Functional features of this protein are currentlyy under investigation. NM41 might be involved in thyroid organogenesis, representingg a candidate gene for investigation of dysgenetic disorders of the thyroidd gland.
