Gianni Bona

Evidence for gene conversion in the generation of extensive polymorphism in the promoter of the growth hormone gene

Abstract The human growth hormone gene (GH-N) is located in a cluster of five highly homologous genes that are coordinately expressed in pituitary (GH-N) and in placental tissues (the chorionic-somatomammotropin-like gene, the GH-variant gene and the two chorionic somatomammotropin genes). Sequence analysis from position –162 to position +100 of the GH-N gene has revealed eight nucleotide polymorphisms with no significant difference in frequency between patients affected by isolated growth hormone deficiency and controls. Remarkably, all these variations are located at positions where the GH-N differs from at least one of the other four homologous genes. The analysis of the twelve GH-N haplotypes originating from the combinations of the eight polymorphisms has revealed that not only single variations, but also nucleotide combinations are identical to those of the other placental genes. These findings suggest that whole stretches of the GH-N gene promoter have been replaced by homologous DNA stretches copied from one of the other four loci by repeated gene-conversion-like events, where the GH-N gene has acted as the recipient and the placental genes as donors of the converted sequences. The presence of a Chi-like element also indicates that the GH-N promoter represents a hot spot of gene conversion. Three of these variations cause, in addition, an amino-acid substitution in the GH-gene-derived transcriptional activator gene whose coding sequence overlaps the GH-N promoter. Thus, a DNA region that serves two distintic functions representing the proximal promoter of a gene and the 5′ coding region of another gene displays an unusually high degree of polymorphism that has probably arisen because of gene conversion.

Short stature and Helicobacter pylori infection in Italian children: prospective multicentre hospital based case-control study

Members of the study group are listed at the end of the article Helicobacter pylori is mainly acquired in childhood,1 but the diseases associated with such infection remain unknown. Scottish and Italian schoolchildren infected with H pylori showed reduced growth in height, 2 3 and H pylori gastritis was found in 55% of French children examined for short stature.4 To evaluate the role of H pylori and socioeconomic factors on growth we compared children with idiopathic short stature with those of normal height. This study was approved by and conducted within the guidelines of the gastric disease section of the Italian Society for Paediatric Gastroenterology and Hepatology (SIGEP). Between April 1996 and March 1997 we recruited 134 consecutive children aged 5-13 years (median 9.8 years) whose height was below the third centile—that is, two standard deviations below the mean height of their peers—from 26 paediatric gastroenterology and endocrinology units in Italy. We individually matched them with children of the same age and sex from the same region whose height was above the 25th centile and who had been referred …

Etiology of Congenital Hypothyroidism

Congenital hypothyroidism (CH) is a condition of thyroid hormone deficiency present at birth. According to the duration of thyroid hormone deficiency, it may be classified into permanent and transient CH. According to the anatomic location of the pathogenic defect, CH may be further classified into primary, secondary (or central), and peripheral CH. The most frequent cause of permanent primary CH is thyroid dysgenesis, which includes thyroid ectopy, agenesis, and hypoplasia. Thyroid dysgenesis is generally sporadic in occurrence, but in about 2 % of cases, mutations in genes PAX8, TTF-2, NKX2.1, and NXK2.5 may be detected. Dyshormonogenesis is the second most common cause and may be caused by mutations in genes encoding the sodium-iodide symporter, thyroperoxidase, hydrogen peroxide generation factors, thyroglobulin, iodothyronine deiodinase, and pendrin. Rare causes of CH include resistance to TSH binding or signaling, central CH, and peripheral CH caused by thyroid hormone syndrome or defects in thyroid hormone transport and metabolism.

Children Obesity, Glucose Tolerance, Ghrelin, and Prader-Willi Syndrome

Abstract Prader Willi syndrome (PWS) is caused by a genomic imprinting disorder. Its major manifestations include childhood-onset hyperphagia and morbid obesity with specific fat distribution, relative hypoinsulinemia, preserved insulin sensitivity, growth hormone (GH) deficiency, hypogonadism, and mild mental retardation. Hyperghrelinemia is a common feature of the syndrome preceding obesity in infancy, with a different pattern of acylated (AG) and unacylated ghrelin (UAG) secretion across PWS nutritional phases. Alterations in the ghrelin system have been investigated in the context of PWS, such as uncontrolled eating, fat accrual, and specific glucose metabolism, probably as compensatory mechanisms. This chapter discusses findings on the role of ghrelin and obestatin in these PWS clinical features, paying particular attention to the regulation of insulin secretion and sensitivity from childhood to adulthood. The regulation of the ghrelin system by new treatments for hyperphagia and obesity in PWS has been also addressed.

Hormones and Gastrointestinal Function

Development is a continuous process. Nutrition, environment and stress modulate development through gene expression in an epigenetic manner. Prenatal and perinatal nutrition can be imprinting factors and turn on different genes that provide different phenotypes, such as the thrifty phenotype [1]. Indeed, the nutritional support of gastrointestinal growth and function is an important tool in the clinical care of newborn babies, in particular preterm neonates. Before birth, although amniotic fluid is not the main source of nutrition for the fetus, it contributes up to 15% of fetal nutritional requirements and plays a key role in its development and maturation [2, 3]. Accordingly, by 20 weeks of gestation, the anatomy of the fetal gut resembles that of the term neonate. However, the process of intestinal absorption is only partially mature before 26 weeks of gestation: gastro-entero-pancreatic peptides are secreted at a basal rate and can be completely stimulated or inhibited after delivery, in particular through contact with nutrients [4, 5]. At the age of 2 years, the intestine is fully functional [6]. Gut hormones, peptides, and growth factors clearly have a role in gut growth after birth and directly and indirectly mediate the trophic actions of enteral nutrition in a manner that is still incompletely understood [5]. By contrast, hormones and growth factors, which are present in breast milk, also seem to exert trophic activities on gut development and immune function. The interplay is complex [1, 3]. Little is known about the development of these regulatory systems in the human neonate and, as a consequence, premature infants experience significant morbidity and mortality associated with feeding problems [6]. Present clinical nutritional support for preterm babies consists of enteral and parenteral nutrition but both have associated complications [6, 7]. Since enteral feeding is important for gut development, acute or chronic gastrointestinal diseases could be caused by feeding with formula rather than human breast milk. Formula milks contain higher amounts of proteins and lack many endogenous hormones and growth factors [5, 6, 8]. A better understanding of factors linked to gastrointestinal function and energy metabolism could result in improved strategies for supporting nutrition of preterm newborns as well as their later development.

Ghrelin Regulation in Epilepsy

Epilepsy is one of the most common neurological problems worldwide affecting approximately 1% of the population (Browne & Holmes, 2000; Chang & Lowenstein, 2003). It is characterized by recurrent unprovoked behavioural seizures (Beck & Elger, 2008). In recent decades, the relationship between epilepsy and the neuroendocrine system has gained a great deal of interest and many researchers as neurologists, endocrinologists and basic scientists have investigated it. The main issue is whether hormonal changes in relation to epilepsy are due to seizures activity per se or to consequential effects of antiepileptic drugs. To understand the far-reaching effects of epilepsy and antiepileptic medications on hormonal system and vice versa, several studies have been recently performed. Their results are interesting but still controversial and the neuroendocrine regulation of epilepsy is far to be clearly explained. However, considering that a role of hormones in epilepsy is known and in part well described, this chapter would firstly review the endocrine regulation mediated by sex hormones, prolactin (PRL), growth hormone (GH), thyrotropin-releasing hormone (TRH), adrenocortical axis and neuropeptide Y (NPY). More recently, also other new hormones have been investigated in this field, bringing to light ghrelin. Ghrelin is a 28 amino acid peptide predominantly produced by the stomach (Kojima et al., 1999). It was discovered as the first natural ligand of the orphan growth hormone segretagogues receptor 1a (GHS-R1a), which exerts, through its activation, a strong GH-releasing activity (Arvat et al., 2001; Howard et al., 1996; Kojima et al., 1999; Kojima & Kangawa, 2005; van der Lely et al., 2004). It also influences glucose and insulin metabolism and controls food and energy intake through many neuroendocrine systems (van der Lely et al., 2004). Furthermore, several evidences suggest that ghrelin not only plays a metabolic role but it is also involved in sleepwake regulation, affective status, learning and memory processes (Steiger et al., 2011; van der Lely et al., 2004). Besides, the recent discovery of ghrelin has also provided an important insight to the neuroendocrine knowledge in epilepsy. In fact, a relationship between ghrelin and epilepsy has been already shown in animal and human models, although the results are sometimes conflicting. Thus, this chapter would secondly describe the intriguing ghrelin role in relation to seizures activity and discuss open questions and future perspectives.