Institute of Child Health

International researchers, including a team at Great Ormond Street Hospital and the UCL Institute of Child Health, have discovered a new cause for thyroid hormone deficiency, or hypothyroidism. This common endocrine disorder is typically caused by problems of the thyroid gland, and more rarely, by defects in the brain or the pituitary gland (hypophysis). However, a new cause of the disease has been discovered from an unsuspected source and is reported in the journal Nature Genetics.

The scientists, led by McGill University Professor Daniel Bernard, Department of Pharmacology and Therapeutics in the Faculty of Medicine, identified a new hereditary form of hypothyroidism that is more prevalent in males than in females. This sex bias shone a light on where to look for the underlying cause.

Researchers used state-of-the-art DNA sequencing technologies to see if they could identify a genetic anomaly in families where more than one member of the family had the condition.  The genes from one patient family from Great Ormond Street Hospital who took part in the study were analysed by Professor Mehul T Dattani, Clinical and Academic Lead in Paediatric Endocrinology, at Great Ormond Street Hospital and the ICH, in collaboration with the team of Professor Krishna Chatterjee at Addenbrooke’s Hospital and the University of Cambridge.

Great Ormond Street Hospital was one of a number of institutions that became involved in the international collaboration after both the UK and Dutch group (led by Professor Jan Maarten Wit) independently identified mutations in a gene called immunoglobulin superfamily, member 1 (IGSF1).  Once that mutation had been identified, it was important to determine whether the observed mutation might cause the disorder.  To do so, other families with more than one person affected needed to be studied.  

Researchers in the Netherlands, the UK, Italy and Australia who were following similar families found that affected males all had mutations in their IGSF1 gene. Overall, the team identified 11 families with 10 different mutations in IGSF1.

"We went on to show that mutations in IGSF1 block the protein it encodes from moving to the cell surface, where it normally functions", explained Beata Bak, McGill PhD student and the paper's co-first author. "We also observed that the pituitary glands of mice lacking IGSF1 had reduced levels of the receptor for a brain-derived hormone known as thyrotropin-releasing hormone (TRH). If we think of TRH as a key, then its receptor is the lock into which the key fits to produce its effects. Our results suggest that in the absence of IGSF1, the pituitary gland becomes less sensitive to the brain's instructions to secrete thyroid-stimulating hormone (TSH). As a result, the thyroid gland receives a reduced impetus to produce thyroid hormones."

The group's findings are significant as IGSF1 mutations cause a variable, though principally mild, form of hypothyroidism that would likely escape detection by most perinatal thyroid function screening methods. In addition, since the IGSF1 gene is highly polymorphic, there may be many individuals (boys and men, in particular) in the general population with presently undetected, but clinically significant hypothyroidism.
Symptoms of the disease include fatigue, weight gain, cold sensitivity, and muscle weakness. If left untreated, hypothyroidism increases the risk of developing heart disease. In infants, hypothyroidism can cause neurodevelopmental delay and, in extreme circumstances, cretinism.

“Understanding the causes of diseases such as hypothyroidism is important.  As a result of this research we will be able to carry out a simple test to identify carriers of IGSF1 gene mutations or variants who might benefit from thyroid hormone replacement therapy,” said Professor Mehul T Dattani.

“We have an active research programme at Great Ormond Street Hospital and the UCL Institute of Child Health through which we are trying to establish the role that genes play in the development of rare endocrine disorders including hypothyroidism and hypopituitarism.  We would not be able to drive forward progress if families were not willing to get involved in our studies – so we are very grateful to patients who get involved in studies such as this one.”

Contact information

For further information please contact Jenny Gimpel at the GOSH-ICH Press Office on 020 7239 3178, email jenny.gimpel@gosh.org.