Study of monogenic forms of obesity has demonstrated the pivotal role of the central leptin-melanocortin pathway in controlling energy balance, appetite and body weight . The majority of loss-of-function mutations (mostly recessive or co-dominant) have been identified in genes that are directly involved in leptin-melanocortin signaling. These genes, however, only explain obesity in<5% of cases, predominantly from outbred populations . We previously showed that, in a consanguineous population in Pakistan, recessive mutations in known obesity-related genes explain ~30% of cases with severe obesity. These data suggested that new monogenic forms of obesity could also be identified in this population. Here we identify and functionally characterize homozygous mutations in the ADCY3 gene encoding adenylate cyclase 3 in children with severe obesity from consanguineous Pakistani families, as well as compound heterozygous mutations in a severely obese child of European-American descent. These findings highlight ADCY3 as an important mediator of energy homeostasis and an attractive pharmacological target in the treatment of obesity.
Background/Aims: Kabuki syndrome (KS) is a rare genetic malformation syndrome, resulting in characteristic features such as short stature. We investigate whether growth hormone (GH) treatment increases linear height and influences body proportions in KS children. Methods: In this prospective study, 18 genetically confirmed prepubertal KS children (9 females and 9 males) aged from 3.8 to 10.1 years (mean 6.8 ± 2.1 years) were treated with recombinant human GH (rhGH) for 1 year. Calculations for height, height velocity, BMI, sitting height, and subischial leg length were made. Bone age, insulin-like growth factor (IGF-I), and IGF binding protein 3 (IGFBP-3) were also measured. Results: This study showed an increase in height standard deviation score (SDS) for the whole group from –2.40 to –1.69 (p < 0.05) after 1 year of rhGH treatment. The change in height SDS within 1 year was >0.7 SDS for 10 subjects and >0.5 SDS for 3 subjects. The mean IGF-I SDS at the start of the study was –0.70 (±1.07), which increased after 12 months to 1.41 (±0.91) (p < 0.05). KS children who received rhGH at a younger age displayed significantly greater increases in height than those who started when they were older. The same was true for both gene mutation KMT2D versus KDM6A and for GH deficiency versus non-GH deficiency KS children (p < 0.05). Throughout the course of rhGH treatment, the subjects’ body proportions remained normal. Conclusions: All participants experienced catch-up growth during the year of rhGH treatment, but without an influence on body proportions.
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