RESUMEN
BACKGROUND: Although leptin/melanocortin pathway pathologies in hypothalamus are thought to be the main cause of early-onset obesity and hyperphagia in PWS and BBS, the exact mechanism is still not known. OBJECTIVE: To measure serum concentrations of a-MSH, BDNF and AGRP in a group of children with BBS or PWS. METHODS: We recruited 12 subjects with PWS, 12 subjects with BBS, 28 obese controls (OC) and 26 lean controls (LC) matched for age, sex and puberty. Serum a-MSH, BDNF and AGRP levels were measured by the ELISA method. RESULTS: The mean a-MSH level was lower in PWS than those of OC and LC (3729 ± 1319, 5211 ± 829 and 5681 ± 565 pg/ml, respectively, p < 0.001), and mean a-MSH was lower in OC than LC (p < 0.05). The mean BDNF level of PWS was higher than those of OC and LC (565 ± 122, 482 ± 102 and 391 ± 74 pg/ml, respectively, p < 0.001). On the other hand, mean a-MSH level of BBS was lower than those of OC and LC (4543 ± 658, 5211 ± 829 and 5681 ± 565 pg/ml, respectively, p < 0.001), and mean a-MSH was lower in OC than LC (p < 0.05). The mean BDNF level of BBS was higher than those of OC and LC (583 ± 115, 482 ± 102 and 391 ± 74 pg/ml, respectively, p < 0.001). Additionally, both in PWS and BBS, the mean BDNF level was higher in OC than LC (p < 0.01). Regarding AGRP level, there was no difference both in BBS and PWS compared to OC. CONCLUSION: We found that the serum a-MSH levels of PWS and BBS groups are significantly lower compared to those of obese and lean controls. Therefore, we can speculate that the circulating a-MSH level does properly reflect its central production, and the serum a-MSH level might be a good biomarker to detect a-MSH deficiency in individuals suspected to have BBS or PWS, and also in those with POMC, PCSK1, and LEPR deficiency.
Asunto(s)
Factor Neurotrófico Derivado del Encéfalo , alfa-MSH , Proteína Relacionada con Agouti/metabolismo , Niño , Humanos , Obesidad/metabolismo , Síndrome , alfa-MSH/metabolismoRESUMEN
Loss-of-function DCAF17 variants cause hypogonadism, partial alopecia, diabetes mellitus, mental retardation, and deafness with variable clinical presentation. DCAF17 pathogenic variants have been largely reported in the Middle Eastern populations, but the incidence in American families is rare and animal models are lacking. Exome sequencing in 5 women with syndromic hypergonadotropic hypogonadism from 2 unrelated families revealed novel pathogenic variants in the DCAF17 gene. DCAF17 exon 2 (c.127-1G > C) novel homozygous variants were discovered in 4 Turkish siblings, while 1 American was compound heterozygous for 1-stop gain variant in exon 5 (c.C535T; p.Gln179*) and previously described stop gain variant in exon 9 (c.G906A; p.Trp302*). A mouse model mimicking loss of function in exon 2 of Dcaf17 was generated using CRISPR/Cas9 and showed female subfertility and male infertility. Our results identify 2 novel variants, and show that Dcaf17 plays a significant role in mammalian gonadal development and infertility.