Thyroid dysgenesis is the most common cause of congenital hypothyroidism, a relatively frequent disease affecting 1 in 3000-4000 newborns. Whereas most cases are sporadic, mutations in transcription factors implicated in thyroid development have been shown to cause a minority of cases transmitted as monogenic Mendelian diseases. PAX8 is one of these transcription factors, and so far, five mutations have been identified in its paired domain in patients with thyroid dysgenesis. We have identified a novel mutation of PAX8, in the heterozygous state, in a father and his two children both presenting with congenital hypothyroidism associated with an in-place thyroid of normal size at birth. In addition, one of the affected siblings displayed unilateral kidney agenesis. The mutation substitutes a highly conserved serine in position 54 of the DNA-binding domain of the protein (S54G mutation) by a glycine. Functional analyses of the mutant protein (PAX8-S54G) demonstrated that it is unable to bind a specific cis-element of the thyroperoxidase gene promoter in EMSAs and that it has almost completely lost the ability to act in synergy with Titf1 to transactivate transcription from the thyroglobulin promoter/enhancer. These results indicate that loss of function mutations of the PAX8 gene may cause congenital hypothyroidism in the absence of thyroid hypoplasia.

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These kindreds represent a distinct etiological entity of autosomal dominant RTSH. According to the clinical presentation of these families, genetic causes of mild hyperthyrotropinemia in the general population may be more common than currently appreciated.

Objective: The LH/chorionic gonadotrophin receptor (LHCGR) is a G protein-coupled receptor (GPCR) that plays a central role in male sexual differentiation, regulation of ovarian follicular maturation, ovulation and maintenance of corpus luteum and pregnancy, as well as maintenance of testicular testosterone production. Mutations in the LHCGR gene are very rare. The aim of this work was to study the clinical and molecular characteristics of a rare familial LHCGR mutation. Methods: Five affected members of a family, including a phenotypically female, but genotypically male (46,XY), patient with Leydig cell hypoplasia type 1 and four genotypically female siblings with reproductive abnormalities, were studied genetically. Cell trafficking studies as well as signalling studies of mutated receptor were performed. Results: The five affected patients were all homozygous for a novel mutation in the LHCGR gene, a deletion of guanine in position 1850 (1850delG). This resulted in a frameshift affecting most of the C-terminal intracellular domain. In vitro studies demonstrated that the 1850delG receptor was completely incapable of transit to the cell membrane, becoming trapped within the endoplasmic reticulum. This could not be rescued by small-molecule agonist treatment or stimulated intracellularly by co-expression of a yoked human chorionic gonadotrophin. Conclusions: This novel LHCGR mutation leads to complete inactivation of the LHCGR receptor due to trafficking and signalling abnormalities, which improves our understanding of the impact of the affected structural domain on receptor trafficking and function.

Congenital hypothyroidism (CH) is a relatively frequent and potentially severe disease. It is classically subdivided into: 1) thyroid dysgenesis (TD), a defect in the organogenesis of the gland leading to hypoplastic, ectopic, or absent thyroid gland; or 2) thyroid dyshormonogenesis, a defect in one of the biochemical mechanisms responsible for thyroid hormone synthesis. Most cases of TD are sporadic, although familial occurrences have occasionally been described. Recently, several genes have been implicated in a small proportion of TD, but, in the majority of the cases, the etiology remains unknown. PAX8 is a transcription factor involved in thyroid development. So far, three loss-of-function mutations of PAX8 have been described, two in sporadic cases and one in familial thyroid hypoplasia. Here, we describe a novel mutation of PAX8 causing autosomal dominant transmission of CH with thyroid hypoplasia. The mutation consists of the substitution of a tyrosine for cysteine 57 in the paired domain of PAX8. When tested in cotransfection experiments with a thyroid peroxidasse promoter construct, the mutant allele was unable to exert its normal transactivation effect on transcription. Our results give further evidence that, contrary to the situation in knockout mice, haplo-insufficiency of PAX8 is a cause of CH in humans.