| Congenital hypothyroidism (CH) is the most frequent endocrinopathy (1:3,000 newborns). In 80% of cases, CH is due to defects in the embryological development or migration of the thyroid gland. The molecular basis of thyroid dysgenesis is poorly understood, it can only be characterised in less than 1% of patients. Strikingly, no effector/mediator of thyroid migration has been characterised at the molecular level. Recently we identified a novel transcript using serial analysis of expression, named NM41. It is highly expressed in thyroid and at a lower level in lung and kidney. The gene is located on human chromosome 16 and computerised analysis of the promoter shows regulatory elements for transcription factors expressed very early in thyroid development. Functional in silico analysis of the corresponding protein indicates that is a member of the cystine-knot family of proteins (known to be involved in embryological development). All data point to a role of NM41 in development and/or migration of the thyroid gland. The aim of the project is to elucidate the function and regulation of NM41 and to define and investigate the corresponding aetiology for human thyroid disease. Approach: A mouse knockout model for NM41 will be developed to study the role in (thyroid) development and function. The human NM41 promoter will be characterised in vitro by transfection of promoter-reporter constructs in both thyroidal and non-thyroidal cell lines. We have DNA and clinical data of 200 patients with congenital hypothyroidism available that will be used to analyse the NM41 gene in relevant candidate patients. Expected results: This study on the novel thyroid specific gene and protein NM41 will unravel its function in thyroid physiology. Together with the genetic screening of patients, it will establish the role of NM41 in thyroid disease. |
