NEW YORK (GenomeWeb) – A team from the UK, the Netherlands, and Ireland has identified a form of inherited obesity and type 2 diabetes that appears to stem from a mutation in a single enzyme-coding gene.
As they reported online yesterday in PLOS One, the researchers did exome sequencing on members of a consanguineous family affected by a condition characterized by extreme obesity, type 2 diabetes, intellectual disability, and other features. Their search led to truncating mutations affecting both copies of a gene that codes for a peptide-processing enzyme called carboxypeptidase E.
That enzyme normally plays a role in regulating hormone and neuropeptide peptides, the team explained. And past mouse studies suggest that mutations that alter the enzyme's ability to regulate such peptides can throw off appetite control, normal glucose metabolism, and other physiological processes.
"There are now an increasing number of single-gene causes of obesity and diabetes known," corresponding author Alexandra Blakemore, a diabetes, endocrinology, and metabolism researcher at the Imperial College of Medicine, said in a statement.
"We don't know how many more have yet to be discovered, or what proportion of the severely obese people in our population have these diseases — it is not possible to tell just by looking," Blakemore added, explaining that such inherited conditions can affect individuals' bodies and their ability to appropriately respond to hunger and fullness signals.
In an effort to track down new genes that contribute to inherited, single-gene forms of obesity, the researchers performed exome sequencing on members of a Sudanese family found through a genetic obesity clinic at a UK hospital.
Using the Agilent SureSelectXT Human All Exon V4+UTR kit, the team isolated protein-coding DNA from an affected family member — a morbidly obese 21-year-old woman with childhood-onset obesity, type 2 diabetes, intellectual disability, and reproductive problems — along with her mother and sister.
After sequencing these exomes with the Illumina HiSeq 2500, the researchers scrutinized the sequences for single nucleotide changes, small insertions and deletions, and copy number variants.
The search ultimately led to a truncating frameshift mutation in the first exon of the CPE gene. With the help of Sanger sequencing, the team determined that the affected woman carried two copies of this mutation, while her mother, sister, and two brothers had one copy of the altered CPE gene.
Similarly, when researchers used real-time PCR to track expression of the gene in blood samples from family members and female controls, they did not detect CPE transcripts in blood samples from the affected women. A sister with one copy of the mutation had lower-than-usual CPE expression compared to six control individuals.
The study's authors argued that the newly detected mutation, together with those in other genes involved in monogenic forms of obesity, should provide opportunities to find the basis of disease in ever more individuals with inherited obesity.
"Diagnosis is very valuable to the patient. It helps to set realistic expectations, and can help them get the best possible treatment," Blakemore noted, explaining that such diagnoses also make it possible to provide genetic counseling and advice to other members of affected families.