Notably, changes in the PHIP gene also were linked with learning difficulties, the researchers said.
“Our findings suggest that PHIP should be included in genetic testing recommended in clinical guidelines as part of the assessment of severe childhood obesity, particularly in children with developmental delay,” I. Sadaf Farooqi, a professor from the University of Cambridge and the study’s senior author, said in a press release.
The study, “Exome Sequencing Identifies Genes and Gene Sets Contributing to Severe Childhood Obesity, Linking PHIP Variants to Repressed POMC Transcription,” was published in the journal Cell Metabolism.
High-calorie diets and low levels of physical activity can drive obesity in children. However, the researchers noted that, in 40-70% of cases, body weight changes are caused by genetic variations. Finding which genes are involved in body weight regulation is key to developing new therapies that can help halt early obesity onset, the scientists said.
Genetic studies have identified rare mutations that impact proteins involved in the leptin-melanocortin pathway, which is responsible for controlling food intake and body weight.
More than 250 gene sites (loci) linked to body mass index and obesity have been identified in genome-wide association studies (GWAS), which establish the relation between genetic variants and disease traits.
“However, these common variants do not explain why some children develop severe obesity,” said Ines Barroso, PhD, the study’s other co-senior author from the University of Exeter Medical School.
In what researchers called the largest study of the genetics of childhood obesity, Barroso, Farooqi and their teams now explored the causes behind the heritability of obesity. They conducted a genetic screening of individuals with early childhood obesity with unknown cause and compared them with healthy children (controls). In total, the scientists analyzed 2,737 severely obese children of European ancestry and 6,704 healthy volunteers.
Variations in the PHIP, DGKI and ZMYM4 genes were significantly associated with obesity, the results show.
“In this study we identified rare genetic variants that are predicted to lead to faulty genes and that appear to explain a part of this ‘missing heritability’ in severe childhood obesity,” Barroso said.
Mutations in the PHIP gene had already been described in people with developmental delays and intellectual disabilities, often reported to be overweight. By analyzing the obesity cases according to developmental delay, noting its presence or absence, the researchers observed a strong link between PHIP mutations and lags in development.
Next, further experiments were conducted to understand how PHIP variants impacted body weight control. Specifically, the investigators studied 17 rare variants found in children with obesity and healthy controls.
The team observed that, inside the cell, the protein resulting from the PHIP gene activates a gene called POMC, which lowers a person’s appetite after a meal. However, in overweight people, mutations in PHIP impaired its function and lowered the levels of POMC protein. In line with previous data in mice, some PHIP variants were associated with excessive eating (hyperphagia) and early type 2 diabetes.
To test whether mutations in DGKI would lead to changes in body weight, the scientists used mice that had this gene deleted. Notably, DGKI is active in certain regions of the brain and in the thyroid, which makes it a likely candidate to be involved in metabolism regulation, the scientists said.
Mutant mice presented a higher fat mass and fat percentage, as well as lower bone mineral density compared with controls.
In addition, the researchers found that mutations in ZMYM4, which codes for a poorly characterized protein, were associated with severe obesity and mild learning disabilities.
Rare variants in 157 genes predicted to lead to faulty gene activity were more prevalent in the obesity group relative to the healthy controls.
Future studies on these genes might unravel new mechanisms that cause early-onset obesity and could constitute new therapeutic targets, the researchers said.
“These findings may also inform treatment of people with the faulty PHIP gene, as there are medications in clinical trials which work on this pathway in the brain that controls appetite,” Farooqi added.
“Further investigation of the molecular mechanisms affected by rare obesity-associated variants in cells, model organisms, and humans may identify and validate potential targets for weight loss therapy,” the scientists wrote.
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