Mutationsanalyse des Pro-Opiomelanocortin-Gens bei extrem adipösen Kindern und Jugendlichen

Adipositas stellt in der heutigen Gesellschaft ein ernstzunehmendes gesundheitspolitisches Problem dar. Untersuchungen des ?National Center for Health Statistics? zwischen den Jahren 1960-94 zeigen, daß der Anteil an übergewichtigen Personen in den USA in diesem Zeitraum stetig zunahm. Neben ei...

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Bibliographic Details
Main Author: Nottebom, Klaus
Contributors: Hebebrand, Johannes, Prof. Dr. (Thesis advisor)
Format: Doctoral Thesis
Published: Philipps-Universität Marburg 2003
Online Access:PDF Full Text
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Adipositas represents a serious health problem in the current company. Investigations of the ?nationally center for Health Statistics? between the years 1960-94 show that the share in overweight persons in the USA in this period steadily increased. Next to an increased food availability and a removal of the individual physical activity, genetic factors are responsible for the development of an Adipositas. Adoption studies and twin studies show this impressively. Formal gene tables studies belay the genetic contribution to the phänotypic Varianz of the body weight. Moreover the different mouse models brought new recognitions . The Hormone Leptin that is produced by fat cells was identified 1994 and confirmed the thesis of a hormone feed-back mechanism and a central control of the body-weight regulation system. Also in humans relevant mutations in the Leptin gene could be identified in single extremely adipösen persons. Other hormones produced in the ZNS interact with this rule circle and are therefore most likely participant of the body-weight regulation system. The Melanocortin-4-Rezeptor plays herewith an important role. Animal models and studies with humans places that specific mutations of the MC4-Rezeptors are korrelated with obesity. The Proopiomelanocortin gene (POMC) examined here is the matrix for the alpha MSH which is the natural Liganden of the MC4-Rezeptors. Additional to alpha MSH, ACTH ,beta and gamma Lipotropin, beta and gamma MSH, beta Endorphin and the 16-K-Fragment are produced by the POMC gene code. Linkage analyses of threefold different cohort with different ethical origins showed a correlation of plasma-Leptin-levels and the area of the chromosome 2p in which the POMC gene lies. Krude et al. identified 1998 mutations in the POMC gene of two children with pigmentation interferences ACTH deficiency and extreme Adipositas . In this work by means of molekulargenetischer methods (Polymerase-Chain-Reaktion, Single-strand-Conformation-Analysis) i did a Mutationsscreen of the POMC gene at a group 96 extremely obese children. Eight different variants were found by means of Single-strand-Conformation-Analysis and were identified by Sequencing: a 9-bp- insertion(AGC-AGC-GGC) as well as a 18-bp- insertion(AGC-AGC-GGC-AGC-AGC-GGC) between position 6997/6998 of the sequence after Takahashi in the area of the 16-K-Fragments, a 6-basenpaar insertion(GGG-CCC) between position 7304/7305 of the sequence after Takahashi in the area coding for the gamma Lipotropin, two point variants (Guanin to Thymin onOf which one to a chain discontinuance leads (Nonsensemutation), and five bases couple exchanges with which the original amino acid sequence does not change. Assoziationsstudies to these variants in a controll-group of 60 underweight student were negative. Therefore variants in the POMC gene in the studies group examined here have no general influence on the Phänotyp Adipositas.