DNA sequencing discovers new genetic form of obesity and diabetes

Ultra-high-throughput DNA sequencing enabled discovery of a new inherited form of obesity and type 2 diabetes in humans.

Jun 30th, 2015

Researchers at Imperial College London, using ultra-high-throughput DNA sequencing, discovered a new inherited form of obesity and type 2 diabetes in humans.

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A large number of genes are involved in regulating body weight, and there are now over 30 genes known in which people with harmful changes in DNA sequence become extremely overweight. Similarly, there are a number of genes that can, when altered, cause type 2 diabetes. These conditions are inherited through families in exactly the same way as disorders such as cystic fibrosis or Huntington’s disease. It is unclear what proportion of severe obesity and type 2 diabetes is caused by genetic disease.

The research team discovered the new defect by sequencing the DNA (using Illumina's HiSeq25000 ultra-high-throughput platform) of an extremely obese young woman and members of her family. In addition to an increased appetite leading to severe weight problems from childhood, she had type 2 diabetes, learning difficulties, and reproductive problems.

They found that she had inherited two copies of a harmful genetic change that meant she could not make a protein called carboxypeptidase-E (CPE). This is an enzyme that is important in the proper processing of a number of hormones and brain transmitters controlling appetite, insulin, and other hormones important in the reproductive system.

Studies have previously shown that CPE deficiency causes obesity, diabetes, and impaired memory in mice, but no humans with the condition have been found before. CPE deficiency is a recessive condition, so a person would need to inherit the altered genetic sequence from both parents to be affected.

The patient was clinically evaluated by consultant endocrinologist Dr. Tony Goldstone, who runs a specialist genetics obesity clinic at Hammersmith Hospital (London). The patient’s parents are cousins, giving her a relatively high likelihood of inheriting the same genetic change from both parents. She had an older brother with similar symptoms who died at age 21.

“These are serious disorders that affect the body's ability to regulate hunger and fullness signals," says Professor Alex Blakemore from the Department of Medicine at Imperial College London, who led the study. "They are inherited in the just same way as other genetic diseases and the sufferers should not be stigmatized for their condition. They should be offered genetic counseling and specialized lifelong support to allow them as healthy a life as possible."

"Finding a genetic cause for the patient’s problems has helped her and her family to understand and manage her condition better. We can also look at members of her family with one abnormal copy of the gene, to see they are affected in more subtle ways that could increase their risk of obesity," says Dr. Sanne Alsters of the Department of Medicine, who carried out the genetic tests and was first author of the study.

Professor Blakemore says genetic tests should be widely available for patients with severe obesity. “If people are diagnosed with a genetic condition like this one, we can look for other possible symptoms, and offer genetic advice to other family members if they want this. Diagnosis is very valuable to the patient. It helps to set realistic expectations, and can help them get the best possible treatment,” she says.

Full details of the work appear in the journal PLoS One; for more information, please visit http://dx.doi.org/10.1371/journal.pone.0131417.

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