Scientists identify the first patient with a thyroid receptor alpha defect
Researchers from the Cambridge BRC have described the first person with a defect in the thyroid hormone receptor alpha gene (THRA). The findings boost our understanding of the relative roles of alpha and beta thyroid receptors in different tissues, and should help inform the development of drugs specific to each receptor type.
The team, which included Professors Krishna Chatterjee and Sadaf Farooqi from the Diabetes, Obesity, Metabolism and Endocrinology Theme, studied a six-year-old girl with classical signs of low levels of thyroid hormone (hypothyroidism), including delayed growth and development. Unexpectedly, she had near-normal circulating levels of thyroid hormone.
The researchers sequenced the patient’s DNA and identified a de novo mutation (not seen in either parent) in THRA. By computer modelling the corresponding protein structure, they found that this mutation – a change from one amino acid to another at position 403 – caused the receptor to be shortened. This, in turn, means that an inhibitor of the receptor stays bound to it, leaving the receptor permanently ‘off’ and unable to bind thyroid hormone.
On why the patient’s hormone levels were not more deranged, Prof Chatterjee says, “Our observations support the notion that marked hypothyroidism in selected tissues can be present, even when only small changes in circulating thyroid hormone levels are seen, reflecting the divergent roles of alpha and beta receptors.”
This work is published in the following article:
Bochukova E et al. A mutation in the thyroid hormone receptor alpha gene. N Engl J Med. 2012; 366(3):243-9.
Scientists identify cause of severe hypoglycaemia
Research provides the prospect of effective drug treatments for the genetic disorder.
Two DOME members receive inaugural Wellcome Trust Investigator Awards
Two members of the DOME theme, Professor Steve O'Rahilly (theme leader) and Professor Krishna Chatterjee are among the first to be awarded Wellcome Trust Senior Investigator Awards, a prestigious new scheme providing funding for exceptional researchers who demonstrate they are addressing some of the most important questions about health and disease.
Steve O'Rahilly has been awarded £2.2 million over 5 years to study Insulin Resistance: Lessons from Extreme Phenotypes, while Krish Chatterjee has funding of £1.8 million to investigate Disorders of nuclear hormone synthesis and action: genetics and pathophysiology.
Speaking about the awards, Sir Mark Walport, Director of the Wellcome Trust, says "We are demonstrating our confidence in these outstanding individuals by providing longer-term, flexible funding; in return, we expect that they will make significant advances in knowledge in their field and act as ambassadors within the research community, helping us achieve our aim of improving human and animal health."
Rare genetic disorder highlights the importance of selenium
A team led by Professor Krishna Chatterjee has identified a rare genetic disorder that highlights the importance of selenium, a little known trace element, to human health. Although toxic in large amounts, selenium is essential as it is incorporated as the amino acid selenocysteine into some proteins (known as selenoproteins). Using resources provided by the BRC, affected individuals were found to have a variant of the gene SECISBP2 which means they are unable to produce most of the 25 known human selenoproteins. As a consequence, patients have abnormal thyroid function, and develop disorders such as muscular dystrophy (muscle weakness) and male infertility.
This discovery is reported in the Journal of Clinical Investigation
A novel genetic cause of lipodystrophy and the metabolic syndrome
Obesity substantially increases the risk of several serious metabolic diseases, such as diabetes, fatty liver and heart disease, which together are known as the Metabolic Syndrome. This often leads people to believe that fat itself is inherently 'bad' for our health. However, this is far from true, fat tissue is essential for human health and the consequences of having too little can be just as serious as having too much. This is clear from studying a condition called lipodystrophy. Patients with this rare genetic disorder have very little body fat although they have several signs that are usually associated with obesity, such as severe insulin resistance, diabetes and fatty liver.
With funding provided by the BRC, studies led by Dr David Savage have identified two heterozygous frameshift mutations in the perilipin gene (PLIN1) in three families with partial lipodystrophy, severe dyslipidemia, and insulin-resistant diabetes. Subcutaneous fat from the patients was characterized by smaller-than-normal adipocytes, macrophage infiltration, and fibrosis. In contrast to wild-type perilipin, mutant forms of the protein did not increase triglyceride accumulation when expressed heterologously in preadipocytes. These findings define a novel dominant form of inherited lipodystrophy and highlight the serious metabolic consequences of a primary defect in the formation of lipid droplets in adipose tissue. Identifying a new cause of lipodystrophy is also extremely useful clinically as it provides patients with a precise diagnosis.
This work is published in the New England Journal of Medicine
Rare copy number variants cause severe obesity in childhood
We reported the first evidence that copy number variants are responsible for rare cases of extreme childhood obesity. Copy number variants occur where a segment of DNA is duplicated or deleted and they are already known to cause autism and learning difficulties. One of the most common deletions involved the SH2B1 gene, which encodes an essential component of the leptin signalling pathway. Of particular clinical interest is several children with this deletion had been placed on the "at risk" social services register, based on the assumption that inadequate parenting was the cause of their obesity. Our discovery prompted these decisions to be reconsidered and reversed. Such studies are also contributing to the wider debate concerning the biological and social determinants of obesity. This study is published in Nature
Artificial pancreas helps prevent overnight hypoglycaemia in adults and children with Type 1 diabetes
Recent studies have compared the safety and efficacy of overnight closed loop delivery of insulin (using the Artificial Pancreas) with conventional insulin pump therapy in children and adults with type 1 diabetes. Closed loop delivery of insulin halved the time they spent with low blood glucose levels during testing, indicating the Artificial Pancreas improves overnight control of glucose levels and reduces the risk of nocturnal hypoglycaemia. The studies included nights when the subjects went to bed after eating a large evening meal or having done early evening exercise, both of which are challenging to manage with conventional insulin treatment.
BRC-funded researcher Dr Roman Hovorka comments "Hypoglycaemia remains a major challenge, especially during the night, so it's encouraging to see such promising results from our trial using commercially available devices."
Circadian rhythms are controlled by metabolic changes
Research has for the first time identified circadian rhythms in red blood cells. This is significant because circadian rhythms have previously been assumed to be controlled by gene activity; however this clearly is not the whole story as, unlike most of the other cells in the body, red blood cells do not contain DNA.
This research, published in Nature, could provide important insights into health problems associated with disrupting normal circadian rhythms. Dr Reddy, the lead author, comments "The implications of this for health are manifold. We already know that disrupted clocks - for example, caused by shift-work and jet-lag - are associated with metabolic disorders such as diabetes. By furthering our knowledge of how the 24-hour clock in cells works, we hope that the links to these disorders - and others - will be made clearer. This will, in the longer term, lead to new therapies that we couldn't even have thought about a couple of years ago."
You are what your mother ate
A study published in PNAS provides new insight into why children born to mothers with an unhealthy diet during pregnancy are more likely to develop diabetes and other metabolic diseases in later life. The study shows that poor maternal diet is linked to epigenetic changes that reduce the level of Hnf4a, a transcription factor that is important in development and has previously been associated with diabetes. In adults, this effect is specific to pancreatic islets which are responsible for producing insulin. Detailed studies in rats shows poor maternal diet exacerbates the normal aging-related decline in Hnf4a in the pancreatic islets in the offspring. Similar changes are seen in the human pancreas.
The authors conclude that epigenetic changes resulting from poor maternal diet and aging lead to reduced expression of Hnf4a in pancreatic beta cells, reducing insulin production and increasing the risk of diabetes. The findings provide an understanding of how a mother's diet influences the expression of Hnf4a in adult offspring and, consequently, their metabolic health. There are also more general implications as the study proposes an epigenetic mechanism by which foetal programming might influence long term health.
New role for thyroid hormones act in the brain to regulate energy balance
Thyroid hormones are important regulators of energy balance that enable the body to convert the food we eat into energy. Thyroid hormones also regulate body temperature by stimulating specific type of fat cells, called brown fat, to burn energy and boost heat production.
People with hyperthyroidism lose weight because they burn more energy than they consume. Until now it was assumed that much of the increase in energy expenditure (and the subsequent weight loss) was caused by the direct action of thyroid hormones on brown fat.
This new research, published in Nature Medicine, shows that the brain also has an important role in this effect. Specifically that the effects of thyroid hormones on brown fat are mediated via the hypothalamus, a specialized region of the brain that also controls food intake.
"These results open up a potentially important new area of obesity research in which the hypothalamus could be targeted to activate brown fat and promote weight loss. They might also provide a new approach to developing treatment for other diseases such as severe forms of hyperthyroidism or cancer-induced weight loss", comments Professor Toni Vidal-Puig, senior author of the study.
