What genes have we found?

Leptin and Leptin receptor deficiency

The first gene we found was the leptin gene in 1997. Children with a problem in the leptin gene put on weight very quickly and at a very early age. Children who have a faulty gene for the leptin receptor have a very similar range of problems. Both these conditions are very rare.

The children are always hungry, never feel full and will seek out and ask for food even after they have just eaten. The reason for this continual drive to eat is because the children are lacking the hormone leptin which sends messages to the brain to tell us to stop eating because we are full. We can treat leptin deficiency with daily injections of the hormone leptin. The children are now normal weight, and the treatment has also reversed other problems that can be caused by the lack of leptin. Leptin receptor deficiency can be treated with Setmelanotide which is now licensed for this condition in the UK and other countries worldwide.

We have now identified 15 genes which have been shown to cause obesity from an early age. Clinical guidelines now recommend that patients with severe obesity of early onset (before 5 years of age) are offered genetic testing (Styne et al. JCEM 2017).

Below are some examples of genes we have found and their effects in patients with these conditions.

MC4R deficiency

Genetic changes or variants which affect the Melanocortin-4-Receptor (MC4R) gene are the commonest cause of weight problems, with 5% of the children referred to our study having a faulty MC4R gene. The MC4R gene is involved in the same pathway in the brain as leptin, so children often feel hungry all the time. Children (and adults) are often tall with an increase in bone and muscle mass giving them a “big build”. People with a faulty MC4R gene do not burn calories efficiently which also contributes to weight gain. More information on the MC4R gene and treatment for this condition can be found here.

SIM1 and SH2B1 deficiency

Children and adults with SRC-1 deficiency also often feeling constantly hungry. They may be more likely to have bone fractures and may suffer from diarrhoea and thyroid problems. Girls and women with SRC-

1 deficiency may have heavy periods. Some of our patients with SRC-1 deficiency are currently taking part in a clinical trial to see whether a new treatment can help them feel less hungry and lose weight. We will update you on this at the end of the clinical trial.

SRC-1 deficiency

Children and adults with SRC-1 deficiency also often feeling constantly hungry. They are also more likely to have bone fractures than other people the same age, and some people with SRC-1 deficiency may suffer from diarrhoea and thyroid problems. Females with SRC-1 deficiency may have heavy periods.

Some of our patients with SRC-1 deficiency are currently taking part in a clinical trial to see whether a new treatment can help them feel less hungry and lose weight. We will update you on this at the end of the clinical trial.

KSR2 deficiency

Individuals with KSR2 deficiency often feel constantly hungry in childhood but their hunger tends to decrease as they get older. Our studies have shown that adults with KSR2 deficiency have a lower metabolic rate than other people which makes it easier for them to put on weight. We have also shown that people with KSR2 deficiency develop severe Insulin resistance and may benefit from treatment with metformin.

We continue to use the latest technologies available to us to identify further genes which cause severe weight gain. As well as identifying new genes we are also interested in understanding which treatments are beneficial to patients with different gene problems. Information on current treatments can be found here.