Mutationssuche in den Exons 2 und 3 des Galanin-Rezeptor-1-Gens bei extremadipösen Kindern und Jugendlichen, normalgewichtigen Kontrollen und Patientinnenmit Anorexia nervosa oder Bulimia nervosa und die Durchführung von Assoziationsuntersuchungen

Galanin ist ein zentral und peripher exprimiertes Peptid, welches dafür bekannt ist, an verschiedenen Prozessen wie Nahrungsaufnahme, Gewichtskontrolle, Sexualverhalten, Lernen und Gedächtnis, Emotion, Epilepsie, Schmerz, Alkoholabhängigkeit, Motilität des Gastrointestinaltrakts, Herzfrequenz und Bl...

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Bibliographic Details
Main Author: Müller, Hans-Christian
Contributors: Hebebrand, Johannes (Prof. Dr.) (Thesis advisor)
Format: Doctoral Thesis
Published: Philipps-Universität Marburg 2009
Online Access:PDF Full Text
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Galanin is a centrally and peripherally expressed peptide, that is known to be involved in different processes like food intake, weight regulation, sexual behaviour, learning and memory, emotion, seizure, pain transmission, alcohol addiction, gastrointestinal motility, heart rate and blood pressure. So far, three G-protein-linked galanin receptors (GALR1, GALR2 and GALR3) have been cloned from both rat and human. Several studies support a positive correlation of the galaninergic system to the amount of fat consumption and weight control which are mediated through GALR1. These results suggest that GALR1-gene is a candidate-gene for further investigations in human weight regulation [Crawley, 1999; Leibowitz et al., 1998a; Leibowitz et al., 1998b]. To date there are no studies on human GALR1 and its influence on feeding behaviour and weight regulation. Aim of the present work was to screen the coding region of GALR1-gene for mutations and find a possible association in probands with obesity, anorexia nervosa or bulimia nervosa. We screened the coding region of the exons 2 and 3 of GALR1 for mutations [exon 1 Schäuble et al., 2005] using single-strand conformation polymorphism (SSCP) analysis and tested for association in 187 obese children and adolescents (BMI 35.1  6.2 kg/m², age 14.4  3.3, 50.8 % female), 99 patients with anorexia nervosa (BMI 15.7  3.3, age 18.9  5.2, 92.1 % female), 27 patients with bulimia nervosa (BMI 21.7  5.8, age 23.8  4.9, 100 % female) and a group of 106 healthy underweight students (BMI 18.4  1.2 kg/m², age 25.5  3.8, 37.7 % female). In exon 2 we found no sequences different to the wildtype allele in the investigated individuals by using SSCP analysis. In exon 3 of GALR1 we identified a novel single nucleotide polymorphism (SNP) 793AT, that leads to a change in the amino acid sequence (missense mutation) from isoleucin to phenylalanine Ile265Phe. By using amplification refractory mutation system (ARMS)-PCR we identified one homozygous carrier in the group of the healthy underweight students. The percentage of heterozygous carriers for the polymorphism was 10,7 % in obese children and adolescents, 7,07 % in patients with anorexia nervosa, 7,41 % in patients with bulimia nervosa and 7,55 % in the group of underweight students. Association tests showed no significant differences (p > 0,05) for genotype and allele frequencies in the investigated groups. This finding suggests that the identified SNP does not play a major role in weight regulation in the investigated study groups. Further investigations are necessary to clarify participation of human GAL and its receptors in weight regulation and feeding behaviour. There have to be more investigational studies, for example in obesity of adulthood, other ethnical groups etc. to get more comprehensive information about the role of GALR1 in weight regulation. Due to the nearly ubiquitous appearance of galanin and the galanin receptors a contribution in different physiological processes like learning, emotion, seizure or nociception is conceivable. The exact knowledge of mechanism of action of galanin and his three galanin receptors could be a new approach for developing new diagnostic possibilities and treatments of various diseases including metabolic diseases, Alzheimer’s disease, mood disorders, anxiety, alcohol intake, pain and solid tumors. For this reason SNPs in GALR1-gene, as the identified 793AT, should be the focus of further investigations.