Genotype-Phenotype Correlations in Central Precocious Puberty Caused by MKRN3 Mutations.

CONTEXT: Loss-of-function mutations of makorin RING finger protein 3 (MKRN3) are the most common monogenic cause of familial central precocious puberty (CPP). OBJECTIVE: To describe the clinical and hormonal features of a large cohort of patients with CPP due to MKRN3 mutations and compare the characteristics of different types of genetic defects. METHODS: Multiethnic cohort of 716 patients with familial or idiopathic CPP screened for MKRN3 mutations using Sanger sequencing. A group of 156 Brazilian girls with idiopathic CPP (ICPP) was used as control group. RESULTS: Seventy-one patients (45 girls and 26 boys from 36 families) had 18 different loss-of-function MKRN3 mutations. Eight mutations were classified as severe (70% of patients). Among the 71 patients, first pubertal signs occurred at 6.2 ±â€…1.2 years in girls and 7.1 ±â€…1.5 years in boys. Girls with MKRN3 mutations had a shorter delay between puberty onset and first evaluation and higher follicle-stimulating hormone levels than ICPP. Patients with severe MKRN3 mutations had a greater bone age advancement than patients with missense mutations (2.3 ±â€…1.6 vs 1.6 ±â€…1.4 years, P = .048), and had higher basal luteinizing hormone levels (2.2 ±â€…1.8 vs 1.1 ±â€…1.1 UI/L, P = .018) at the time of presentation. Computational protein modeling revealed that 60% of the missense mutations were predicted to cause protein destabilization. CONCLUSION: Inherited premature activation of the reproductive axis caused by loss-of-function mutations of MKRN3 is clinically indistinct from ICPP. However, the type of genetic defect may affect bone age maturation and gonadotropin levels.

Gene therapy in the neuroendocrine system: its implementation in experimental models using viral vectors.

Gene therapy, the transfer of genetic material for therapeutic purposes, has undergone an explosive development in the last few years. Within this context, development of gene therapy approaches for the neuroendocrine system, while incipient, has already generated a core of results which emerge as a promising area of research in neuroendocrinology. The present review presents a brief description of the viral vector-based gene delivery systems being currently used in neuroendocrinology, namely the adenoviral and herpes simplex type-1 (HSV-1)-derived vector systems, as well as an updated account of neuroendocrine pathologies for which gene therapy approaches in animal models are being implemented is provided. Current research efforts include treatment of experimental pituitary tumors by adenoviral vector-mediated transfer of the suicide gene for the HSV-1 thymidine kinase, which converts the prodrug ganciclovir into a toxic metabolite. An adenoviral vector encoding the human retinoblastoma suppressor oncogene has also been successfully used to rescue the phenotype of spontaneous pituitary tumors of the pars intermedia in mice. At the hypothalamic level, an adenovirus harboring the cDNA for arginine vasopressin has been used in Brattleboro rats to correct diabetes insipidus for several weeks. The last part of the review outlines the potential of gene therapy to correct age-associated neurodegenerative processes at the neuroendocrine level. Although effective implementation of gene therapy strategies still faces significant technical obstacles, these are likely to be progressively overcome as gene delivery systems are being improved.