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Monoallelic Expression of Mutant Thyroid Peroxidase Allele Causing Total Iodide Organification Defect

Institute of Endocrine Sciences (L.F., N.C., D.M., G.V., C.F., L.P., P.B.-P.), School of Medicine, University of Milan, Milan, Italy; Ospedale Maggiore Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) (L.F., P.B.-P.), 20122 Milan, Italy; and Istituto Auxologico Italiano IRCCS (L.P.), 20145 Milan, Italy

Address all correspondence and requests for reprints to: Paolo Beck-Peccoz, M.D., Institute of Endocrine Sciences (Pad. Granelli), Ospedale Maggiore Istituto di Ricovero e Cura a Carattere Scientifico, Via F. Sforza, 35, 20122 Milan, Italy. E-mail: paolo.beckpeccoz{at}unimi.it.

Mutations in the thyroid peroxidase (TPO) gene lead to severe congenital hypothyroidism due to total iodide organification defect (TIOD). According to the recessive mode of inheritance, patients are homozygous or compound heterozygous for gene mutations. However, about 17% of cases with typical phenotype harbor a single TPO-mutated allele. We present a TIOD family in which the three affected siblings had a single genomic TPO mutation (R693W) inherited from the unaffected father. Other mutations were not found, although all TPO coding exons and exon/intron boundaries were sequenced. Eleven different polymorphisms were found in hetero- or homozygosity in all family members. On the contrary, using retrotranscribed thyroid tissue RNA, all heterozygous polymorphisms and the mutation were homozygous. The distribution of the polymorphisms indicated that only the mutant paternal allele is transcribed at the thyroid tissue level. We excluded the presence of major deletions involving the maternal chromosome at 2p25 and of maternal imprinting or mutations in part of the regulatory regions of the gene.

In summary, we report one family with TIOD due to monoallelic expression of a mutant TPO allele in the thyroid. This mechanism might be generally involved in TIOD cases with a single TPO-mutated allele.

This work was partially supported by Research Funds of Ricerca Corrente of Istituto Auxologico Italiano IRCCS (to L.P.).

Results from this work were presented in part at the 28th Annual Meeting of the European Thyroid Association, Göteborg, Sweden, September 2002.

Abbreviations: CRE, cAMP response element; hTPO, Human TPO; Tg, thyroglobulin; TIOD, total iodide organification defect; TPO, thyroid peroxidase; UTR, untranslated region.

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