New Mutation Associated With Severe Obesity

Becky McCall

July 03, 2015

A single-gene mutation that shuts down production of the carboxypeptidase-E (CPE) enzyme and causes severe obesity and type 2 diabetes, has been identified.

The mutation affects insulin processing and appetite suppression and leads to intellectual disability and reproductive problems, according to the new research published in PLoS One.

The discovery adds to the growing list of single-gene causes for morbid obesity and suggests that "inherited conditions may be much more common among the severely obese than has previously been recognized," said Alex Blakemore, PhD, of Imperial College London, UK, who led the study. Affected people will need lifelong management and access to genetic-counseling services, she added.

"Clinicians treating people with severe obesity should consider the possibility of Mendelian disorders, particularly if obesity is very severe and/or part of a more complex phenotype," she stressed.

This is the first time a homozygous deleterious mutation in CPE leading to a complete shutdown in the production of the enzyme has been discovered. Previous studies have shown that CPE deficiency causes obesity, diabetes, and impaired memory in mice, but no humans affected by the deficiency have previously been identified.

"These are true genetic disorders, inherited through families in a recessive or dominant fashion, as opposed to relatively weak population-based associations such as with common [fat mass and obesity-associated] FTO polymorphisms," Dr Blakemore pointed out.

CPE and Genetic Causes of Obesity

The CPE gene encodes CPE, which is involved in the processing of a number of hormones including insulin and a range of neuropeptides, including those that regulate appetite and the reproductive system.

CPE deficiency is a recessive condition, so an individual would need to inherit the altered genetic sequence from both parents to be affected. In the study, Dr Blakemore and colleagues discuss a young woman who carries two copies of the mutation, and as such, cannot make the enzyme.

The frequency of the CPE gene defect is currently unknown, but Dr Blakemore is currently screening 1500 obese adults to see whether there are other cases.

Referring to the wider issue of genetic causes of obesity, she pointed out that the number of genetic forms of obesity is unknown because obese people are "simply not usually tested."

She added that these conditions are rare in the general population but are much more common in people who are seriously obese.

Referring to unpublished data from her group, she noted that at least 10% of people with a body mass index greater than 50 kg/m2 were likely to have a genetic cause, but this takes into account only genes known to be linked to severe obesity. There are likely many relevant gene defects left to discover, she noted.

"Obese children have been investigated much more than adults. In one study, mutations in just one gene (MC4R) were responsible for one in 20 cases of severe obesity in children," she said. "As sequencing becomes cheaper and more practical for clinical applications, we are finding more and more genetic causes of obesity like this."

An Unusual Case

Dr Blakemore investigated the CPE gene defect in a young Sudanese woman and her family, recruited from the adult genetic obesity clinic at Imperial College Healthcare NHS Trust, London.

The woman has an unusual combination of symptoms, including obesity, diabetes, reproductive-system problems, and learning difficulties.

Describing the patient's situation, Dr Blakemore said she had been obese since childhood and by the age of 20 weighed twice her expected healthy weight. Also, her parents were first cousins. "Initially, it was thought that the patient had an inherited form of obesity called Prader-Willi syndrome, but tests for that condition were negative."

Curious to know the cause of the patient's obesity and help her if possible, the patient's endocrinologist and coauthor, Dr Tony Goldstone, Imperial College Healthcare NHS Trust, referred the young woman to Dr Blakemore for investigation into a potential genetic cause for her condition.

After sequencing the coding and regulatory regions of the genome (the exome), first author Dr Sanne Alsters, also of Imperial College, examined the previously known obesity-causing genes, but drew a blank.

"Then we looked at genes that caused obesity in animal models. CPE is one of these genes, and we saw immediately that the patient had two copies of a particularly damaging genetic change, which meant she was unable to make the CPE enzyme," explained Dr Blakemore.

Clinical Significance of the Finding

The authors write that the patient "exhibits hypogonadotropic hypogonadism and intellectual disability, which may be diagnostic features of CPE deficiency, and so genetic investigation of CPE is warranted in similar cases where other known genetic causes have been excluded, especially with coexistent obesity."

Dr Blakemore stressed that there are several immediate benefits of identifying a genetic cause of disease to patients. "First, we should not underestimate the psychological value of having a diagnosis. This helps families understand and cope with their health problems and may also unlock treatment options not open to undiagnosed patients."

Furthermore, a diagnosis might also shed light on less obvious aspects of the disorder that may be checked for and managed. "Genetic counseling and specialized lifelong support might be offered to allow patients to live as healthy a life as possible."

Finally, in their conclusion, the authors note that ongoing detailed phenotyping of patients and family members with CPE gene defects, "including assessment of circulating levels of hormones regulating glycemia and appetite regulation, would further clarify the role of the CPE prohormone/peptide-processing enzyme in human physiology."

"More generally, the enhanced understanding of disease mechanisms may highlight new targets for treatment or inform management strategies," Dr Blakemore concludes.

Dr Blakemore and coaouthors report no relevant financial relationships.

PLoS One. Published online June 29, 2015. Full text

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