Background: Mutations in the imprinted gene MKRN3 have been described as a common genetic cause of idiopathic central precocious puberty (CPP), in particular in familial cases. However, the exact prevalence of mutations is unknown. Single nucleotide polymorphisms in 2 other imprinted genes, DLK1 and KCNK9, have been associated with age at menarche. We investigated the prevalence of mutations in MKRN3, DLK1, and KCNK9 genes in a cohort of girls with idiopathic CPP. Methods: MKRN3, DLK1, and KCNK9 coding regions were sequenced in 60 girls with idiopathic CPP (familial in 23 cases). Results: Three mutations, including a new one, in MKRN3 were found in 2 familial cases (c.1229G>A; p.Cys410Ter and c.477_485del; p.Pro160Cysfs*14) (8.7%) and in 1 sporadic case (c.982C>T; p.Arg328Cys) (2.8%). We did not find rare variants in DLK1 and KCNK9 genes. Conclusions: (1) The prevalence of MKRN3 mutations in our cohort was similar to that reported in the literature in sporadic cases but lower than previously described in familial ones. This could be due to different inheritance patterns of families studied; (2) we expanded the phenotype of MKRN3 defects describing 3 more patients with MKRN3 mutations; and (3) point mutations in DLK1 and KCNK9 at least do not seem to be a common cause of CPP in girls.

We showed that girls with central precocious puberty had lower peripheral levels of MKRN3 compared to age-matched pairs and that they negatively correlated to gonadotropins, estrogen, and BMI. Our findings support the MKRN3 involvement in central precocious puberty also in absence of deleterious mutations, although our sample size is small. In addition our data suggest the role of MKRN3 in the complex mechanism controlling puberty onset and its interaction with other factors affecting puberty such as nutrition.

Introduction Lysosomal storage diseases (LSDs) are rare inherited metabolic diseases characterized by an abnormal accumulation of various toxic materials in the cells as a result of enzyme deficiencies leading to tissue and organ damage. Among clinical manifestations, cardiac diseases are particularly important in Pompe glycogen storage diseases (PD), in glycosphingolipidosis Fabry disease (FD), and mucopolysaccharidoses (MPS). Here, we evaluated the occurrence of aortopathy in knock out (KO) mouse models of three different LSDs, including PD, FD, and MPS IIIB. Methods We measured the aortic diameters in 15 KO male mice, 5 for each LSD: 5 GLA-/mice for FD, 5 NAGLU-/mice for MPS IIIB, 5 GAA-/mice for PD, and 15 wild type (WT) mice: 5 for each strain. In order to compare the aortic parameters between KO and WT mice deriving from the same colonies, different diameters were echocardiographically measured: aortic annulus, aortic sinus, sino-tubular junction, ascending aorta, aortic arch and descending aorta. Storage material content and aortic defects of the KO mice were also analyzed by histology, when available. Results Compared to their correspondent WT mice: GAA-/mice showed greater diameters of ascending aorta (1.61mm vs. 1.11mm, p-value = 0.01) and descending aorta (1.17mm vs

Background: Recently, mutations of makorin RING finger protein 3 (MKRN3) have been identified in familial central precocious puberty (CPP). Serum levels of this protein decline before the pubertal onset in healthy girls and boys and are lower in patients with CPP compared to prepubertal matched pairs. The aim of our study was to investigate longitudinal changes in circulating MKRN3 levels in patients with CPP before and during GnRH analogs (GnRHa) treatment. Methods: We performed a longitudinal prospective study. We enrolled 15 patients with CPP aged 7.2 years (range: 2–8) with age at breast development onset < 8 years and 12 control girls matched for the time from puberty onset (mean age 11.8 ± 1.2 years). Serum values of MKRN3, gonadotropins, and 17β-estradiol were evaluated before and during treatment with GnRHa (at 6 and 12 months). The MKRN3 gene was genotyped in CPP patients. In the girls from the control group, only basal levels were analyzed. Results: No MKRN3 mutations were found among CPP patients. MKRN3 levels declined significantly from baseline to 6 months of GnRHa treatment (p = 0.0007) and from 6 to 12 months of treatment (p = 0.003); MKRN3 levels at 6 months were significantly lower than in the control girls (p < 0.0001). Conclusions: We showed that girls with CPP had a decline in peripheral levels of MKRN3 during GnRHa treatment. Our data suggest a suppression of MKRN3 by continuous pharmacological administration of GnRHa.