New cause of thyroid hormone deficiency discovered

November 12, 2012

International researchers, including a team at McGill University, 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 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.

"Our collaborators in the Netherlands had been following a family in which two cousins had an unusual syndrome of hypothyroidisim and enlarged testicles," said Prof. Bernard. "Using state-of-the-art DNA , we identified a mutation in a gene called immunoglobulin superfamily, member 1 (IGSF1), in both boys and their maternal grandfather. As one of few labs in the world studying this gene, we initiated a collaboration to determine whether the observed mutation might cause the disorder. At the time, the IGSF1 gene was known to be active in the pituitary gland, but its function was a mystery".

"Shortly after, we were contacted independently by a second group of researchers, studying a second family, in which two young brothers suffered from hypothyroidism and also harbored a mutation in the IGSF1 gene, though it was a different mutation than that observed in the Dutch family," said Prof. Bernard, "The fact that there were two unrelated families with the same male-biased clinical syndrome and mutations in the same gene strongly suggested that the mutations played a causal role in hypothyroidism".

The groups reached out to researchers in the Netherlands, the UK, Italy and Australia who were following similar families and 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 Ph.D. 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 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 methodologies. 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, can cause neurodevelopmental delay and, in extreme circumstances, cretinism.

"A simple test could identify carriers of IGSF1 gene mutations or variants who might benefit from replacement therapy. Our results highlight a fundamental role for this protein in how the brain and pituitary gland control thyroid function and therefore the whole body metabolism. We hope our work will inspire new research on IGSF1's function in the under various physiological and pathophysiological conditions", said Prof. Bernard.

Explore further: ATA: mutation in X-linked gene tied to central hypothyroidism

Related Stories

ATA: mutation in X-linked gene tied to central hypothyroidism

September 25, 2012
(HealthDay)—Mutations in the X-linked immunoglobulin superfamily member 1 (IGSF1) gene, which encodes a pituitary-enriched plasma membrane glycoprotein, may play a role in central hypothyroidism, testicular enlargement, ...

Researchers grow pituitary glands from embryonic stem cells

November 10, 2011
(Medical Xpress) -- A new study published in Nature reports that scientists have been able to grow working pituitary glands from embryonic stem cells from mice. When these were transplanted into mice with defects in the pituitary ...

Mild thyroid dysfunction in early pregnancy linked to serious complications

June 23, 2012
Even moderate thyroid dysfunction during early pregnancy significantly increases the risk of serious complications, underscoring the need for universal screening in the first trimester, a new study finds. The results will ...

Recommended for you

Scientists identify new way cells turn off genes

July 19, 2017
Cells have more than one trick up their sleeve for controlling certain genes that regulate fetal growth and development.

South Asian genomes could be boon for disease research, scientists say

July 18, 2017
The Indian subcontinent's massive population is nearing 1.5 billion according to recent accounts. But that population is far from monolithic; it's made up of nearly 5,000 well-defined sub-groups, making the region one of ...

Mutant yeast reveals details of the aberrant genomic machinery of children's high-grade gliomas

July 18, 2017
St. Jude Children's Research Hospital biologists have used engineered yeast cells to discover how a mutation that is frequently found in pediatric brain tumor high-grade glioma triggers a cascade of genomic malfunctions.

Late-breaking mutations may play an important role in autism

July 17, 2017
A study of nearly 6,000 families, combining three genetic sequencing technologies, finds that mutations that occur after conception play an important role in autism. A team led by investigators at Boston Children's Hospital ...

Newly discovered gene variants link innate immunity and Alzheimer's disease

July 17, 2017
Three new gene variants, found in a genome wide association study of Alzheimer's disease (AD), point to the brain's immune cells in the onset of the disorder. These genes encode three proteins that are found in microglia, ...

Newly identified genetic marker may help detect high-risk flu patients

July 17, 2017
Researchers have discovered an inherited genetic variation that may help identify patients at elevated risk for severe, potentially fatal influenza infections. The scientists have also linked the gene variant to a mechanism ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.