Common Variations in Endocrine Genes in Relation to Growth and Body Composition: Studies in childhood and adolescence

Growth and changes in body composition during childhood and adolescence are regulated and influenced by multiple factors. Among the well-known important hormonal systems are the growth hormone – insulin-like growth factor I (IGF-1) axis, sex steroids and glucocorticoids. Environmental factors like a safe environment, the absence of disease and sufficient nutritional intake are equally important. Another important factor associated with postnatal growth and body composition is size at birth. The non-environmental factors are more or less inheritable. Variation in genetic background among individuals determines to a large extent phenotypic outcome. Genetic polymorphisms are assumed to play an important role in gene expression and explaining heritability. This thesis describes common variations, polymorphisms, in several endocrine genes in relation to growth and body composition. The studies focus on polymorphisms in the IGF-1 gene, the glucocorticoid receptor (GR) gene, the estrogen receptor ï¡ (ERï¡ or ESR1) gene and the androgen receptor (AR) gene. Most studies were performed in two large cohorts of healthy children and adolescents, who grew up in the same area of the Netherlands, but were born with an interval of approximately 20 years. One study also describes the results of a study in a group of children born small for gestational age (SGA) without catch up growth

Rapid dephosphorylation of p107 following UV irradiation

In response to UV irradiation, mouse NIH3T3 fibroblasts transiently arrest predominantly in the G1 phase of the cell cycle. Here, we investigate the role of the retinoblastoma-related pocket proteins in this biological process. We report here that UV induces an increase in p107/E2F complexes, shown previously to be repressors of E2F-dependent transcriptional activity. Several lines of evidence indicate that the increase of p107/E2F complexes following UV irradiation is a consequence of rapid dephosphorylation of p107. First, UV-mediated p107 dephosphorylation could be abolished by pretreatment of NIH3T3 fibroblasts with the serine/threonine phosphatase inhibitors calyculin A and okadaic acid. Second, alteration of protein phosphatase 2A holoenzyme composition by over-expression of specific B subunits interfered with UV-mediated dephosphorylation of p107. Consistent with this, p107 could be dephosphorylated in vitro with PP2A. Moreover, dephosphorylation of p107 was shown to be independent of the activity of p53 and p21, as it occurred also in UV-treated p53-null as well as p21-null mouse fibroblasts. We observed a close correlation between the UV dosages required for G1 cell cycle arrest and p107 dephosphorylation. Our data suggest a model in which UV radiation-induced cell cycle arrest depends, at least in part, on the induction of a PP2A-like phosphatase that acts on p107

Androgen receptor gene CAG repeat polymorphism in longitudinal height and body composition in children and adolescents

Epidemiology in Pediatrics and Child Healt

Estrogen receptor-alpha gene polymorphisms and body composition in children and adolescents

Epidemiology in Pediatrics and Child Healt

Absence of clinically relevant growth acceleration in untreated children with non-classical congenital adrenal hyperplasia.

Item does not contain fulltextBACKGROUND/AIMS: In classical congenital adrenal hyperplasia (CAH), elevation of adrenal androgens leads to accelerated growth and bone maturation with compromised adult height. In untreated children with non-classical CAH (NC-CAH), in which adrenal androgens are generally only slightly increased, growth velocity may not be significantly elevated. METHODS: Twenty-four patients were included and divided into a symptomatic and an asymptomatic group. Height was expressed as height standard deviation scores (HSDS) and corrected for target height (HSDS-THSDS). Bone maturation was expressed as bone age acceleration (BA(c) = bone age - calendar age). Linear mixed models with random factor patient were used for the analysis of growth and bone age. RESULTS: In symptomatic patients (n = 17), HSDS-THSDS only slightly increased by 0.06 SDS per year (95% CI 0.02-0.10). Mean BA(c) was 2.21 years (SDS 0.66, p < 0.0001). In asymptomatic patients (n = 7), no significant growth acceleration or BA(c) was found. CONCLUSIONS: In untreated NC-CAH children, growth acceleration is small and generally not visible on their growth charts. BA(c) is more pronounced. Therefore, the absence of an increase in growth velocity does not exclude the diagnosis of NC-CAH. When considering this diagnosis, bone age acceleration should also be taken into account.6 p

Copy number variants in patients with short stature

Height is a highly heritable and classic polygenic trait. Recent genome-wide association studies (GWAS) have revealed that at least 180 genetic variants influence adult height. However, these variants explain only about 10% of the phenotypic variation in height. Genetic analysis of short individuals can lead to the discovery of novel rare gene defects with a large effect on growth. In an effort to identify novel genes associated with short stature, genome-wide analysis for copy number variants (CNVs), using single-nucleotide polymorphism arrays, in 162 patients (149 families) with short stature was performed. Segregation analysis was performed if possible, and genes in CNVs were compared with information from GWAS, gene expression in rodents' growth plates and published information. CNVs were detected in 40 families. In six families, a known cause of short stature was found (SHOX deletion or duplication, IGF1R deletion), in two combined with a de novo potentially pathogenic CNV. Thirty-three families had one or more potentially pathogenic CNVs (n=40). In 24 of these families, segregation analysis could be performed, identifying three de novo CNVs and nine CNVs segregating with short stature. Four were located near loci associated with height in GWAS (ADAMTS17, TULP4, PRKG2/BMP3 and PAPPA). Besides six CNVs known to be causative for short stature, 40 CNVs with possible pathogenicity were identified. Segregation studies and bioinformatics analysis suggested various potential candidate genes