A new mutation in the leptin receptor (LEPR) gene, leading to loss of the LEPR protein, has been identified in male and female members of an Iranian family, a study reports.
However, the outcomes of the mutation varied with gender — in males, early-onset obesity began to decrease around puberty and they remained fertile; in females, obesity kept increasing and they were infertile.
The study, “Potential role of gender specific effect of leptin receptor deficiency in an extended consanguineous family with severe early-onset obesity,” was published in the European Journal of Medical Genetics.
Leptin and its receptor LEPR are involved in the metabolism of fat, and in maintaining an energetic equilibrium (homeostasis) in our cells. A deficiency in LEPR leads to severe obesity from right after birth. Those affected experience severe hunger or hyperphagia — extreme, unsatisfied drive to consume food — as well as an increased risk of infections because of a lower number and activity of immune T-cells.
LEPR deficiency carriers also have problems in development during puberty, the result of a lack of sufficient sex hormones and thyroid dysfunction.
Now, a team of researchers analyzed an extended Iranian family with nine individuals presenting severe early-onset obesity, with ages raging from 3 to 36 years old, to determine whether this was linked with mutations in the LEPR gene. Although rare, deficiency of LEPR since birth is usually caused by mutations on both copies of the LEPR gene.
A DNA analysis using blood cells from the affected family members revealed a mutation in the LEPR gene. This error led to a shift in the gene sequence; as a result, the LEPR protein was not made properly.
Researchers also looked at the body mass index (BMI) — a measure of body fat — of the affected individuals.
The BMI of the two affected males, ages 36 and 32 at the time of the study, showed a weight reduction starting at puberty, around 13 to 15 years old. No effect on fertility was observed, as both had children.
Two affected females, ages 34 and 25, showed an increase in BMI over time and delayed puberty. These two patients had very low levels of anti-mullerian hormone, which reflects a depletion of the ovarian follicles (the fluid-filled sac that contains the egg), resulting in infertility.
The “gender differences between males and females in prognosis and severity of the phenotype observed among the affected members of the same family [have] not been described before,” researchers stated.
Previous animal studies showed that leptin-deficient females are infertile, and that a small number of male mice actually produce offspring. Another study also showed that different genetic backgrounds and variations mitigated the negative impact of leptin deficiency on male reproduction, but not for females.
This evidence could suggest that the mild effect of the LEPR mutation observed in the male family members could present protective genetic variants that are missing in the females.
Overall, “this study supports a gender difference in the manifestation of LEPR deficiency which may potentially be the basis for the different roles of leptin in male and female body weight regulation, with further investigations required to elucidate the effect on reproduction,” the researchers concluded.