Searchable abstracts of presentations at key conferences in endocrinology
Endocrine Abstracts (2008) 15 OC34

SFEBES2008 Oral Communications Thyroid (8 abstracts)

Maternal isodisomy for a novel human FOXE1 gene mutation in syndromic congenital hypothyroidsim

Mireille Castanet 1 , Uma Mallya 2 , Maura Agostini 1 , Catherine Mitchell 1 , Michel Polak 3 , Stephanie Demuth 4 , Lucy Raymond 2 , Mark Gurnell 1 & Krishna Chatterjee 1

1Institute of Metabolic Science and 2Department of Clinical Genetics, Addenbrooke’s Hospital, University of Cambridge, Cambridge, UK; 3INSERM EMI0363, Hospital Necker Enfants-Malades, Paris, France; 4Facharztin fur Humangenetik, Genetische Beratungsstelle, Erfurt, Germany.

Congenital hypothyroidism (CH), occurs with a frequency of one in 3–4000 and is most commonly due (85%) to complete or partial failure of thyroid gland development (dysgenesis). Several transcription factors (TTF-1/Nkx2.1, TTF-2/FOXE1, PAX-8), are highly expressed in the developing rodent thyroid. We first showed that the FKHL15 gene is the human homologue of TTF-2, identifying a homozygous, loss-of-function, mutation in two siblings with CH, thyroid agenesis, cleft palate, choanal atresia and spiky hair, a phenotype that resembles (thyroid agenesis, cleft palate) the murine TTF-2 gene knockout. To date, 3 different homozygous loss-of-function mutations have been described in the human FOXE1 gene.

Here, we report a patient with athyreosis and cleft palate who was homozygous for a novel missense mutation (F137S) in the FOXE1 gene. In vitro studies with the F137S mutant revealed a severe DNA-binding deficit, and an inability to activate transcription with both artificial and natural promoter constructs. However, in contrast to other reported cases of TTF-2 deficiency, sequencing of parental DNA revealed that although the proband’s mother was an unaffected heterozygous carrier of this mutation, the father’s DNA contained only wild type sequence. Microsatellite marker analysis confirmed paternity, and genotyping of 10 microsatellites spanning chromosome 9 demonstrated that the affected child was homozygous for every marker tested. Seven of these were fully informative, and in keeping with origination from a single maternal chromosome 9. Multiplex ligation probe amplification (MLPA) revealed an identical copy number for the patient as for both her mother and sister, excluding paternal allelic deletion. Together, these results confirm complete maternal uniparental disomy (UPD) for chromosome 9, and reduction to homozygosity of the mutant FOXE1 gene locus, leading to the clinical phenotype in the proband. To our knowledge, this is the first reported case of uniparental disomy (UPD) in the context of syndromic CH.

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